Anaplastic lymphoma kinase: Difference between revisions

ALK
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2KUP, 2KUQ, 2XB7, 2XBA, 2XP2, 2YFX, 2YHV, 2YJR, 2YJS, 2YS5, 2YT2, 3AOX, 3L9P, 3LCS, 3LCT, 4ANL, 4ANQ, 4ANS, 4CCB, 4CCU, 4CD0, 4CLI, 4CLJ, 4CMO, 4CMT, 4CMU, 4CNH, 4CTB, 4CTC, 4DCE, 4FNW, 4FNX, 4FNY, 4FNZ, 4FOB, 4FOD, 4JOA, 4MKC, 4TT7, 4Z55, 5FTO, 5AAB, 5AAA, 5J7H, 5AA9, 5IUH, 5IUI, 5IMX, 5FTQ, 5A9U, 5IUG, 5AA8, 5AAC
Identifiers
Aliases	ALK, CD246, NBLST3, anaplastic lymphoma receptor tyrosine kinase, ALK receptor tyrosine kinase, ALK (gene), ALK1
External IDs	OMIM: 105590; MGI: 103305; HomoloGene: 68387; GeneCards: ALK; OMA:ALK - orthologs
Gene location (Human)
Chr.	Chromosome 2 (human)
End	29,921,586 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	72,911,622 bp
RNA expression pattern
	Top expressed in
	sperm; ; testicle; ; ventral tegmental area; ; superior vestibular nucleus; ; internal globus pallidus; ; subthalamic nucleus; ; buccal mucosa cell; ; Brodmann area 23; ; inferior ganglion of vagus nerve; ; middle temporal gyrus;
	Top expressed in
	inferior ganglion of vagus nerve; ; external carotid artery; ; endolymphatic sac; ; perirhinal cortex; ; Jacobson's organ; ; entorhinal cortex; ; Ileal epithelium; ; vasculature of trunk; ; lumbar subsegment of spinal cord; ; choroid plexus of fourth ventricle;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; protein kinase activity; kinase activity; NF-kappaB-inducing kinase activity; protein binding; identical protein binding; ATP binding; transmembrane receptor protein tyrosine kinase activity; protein tyrosine kinase activity;
Cellular component	integral component of membrane; membrane; extracellular exosome; integral component of plasma membrane; intracellular anatomical structure; plasma membrane; protein-containing complex; receptor complex;
Biological process	regulation of apoptotic process; transmembrane receptor protein tyrosine kinase signaling pathway; nervous system development; protein phosphorylation; positive regulation of NF-kappaB transcription factor activity; cell population proliferation; protein autophosphorylation; signal transduction; neuron development; peptidyl-tyrosine phosphorylation; NIK/NF-kappaB signaling; phosphorylation; brain development; hippocampus development; adult behavior; swimming behavior; regulation of cell population proliferation; regulation of dopamine receptor signaling pathway; response to environmental enrichment; regulation of neuron differentiation; positive regulation of dendrite development;
	Sources:Amigo / QuickGO
Orthologs
	238
	11682
	ENSG00000171094
	ENSMUSG00000055471
	Q9UM73
	P97793
	NM_004304; NM_001353765
	NM_007439
	NP_004295; NP_001340694
	NP_031465
	Wikidata
View/Edit Human	View/Edit Mouse

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Latest revision as of 01:24, 9 March 2024

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.^[5]^[6]

Identification

Anaplastic lymphoma kinase (ALK) was originally discovered in 1994^[5]^[7] in anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) chromosomal translocation that generates the fusion protein NPM-ALK, in which the kinase domain of ALK is fused to the amino-terminal part of the nucleophosmin (NPM) protein. Dimerization of NPM constitutively activates the ALK kinase domain.^[5]^[7]

The full-length protein ALK was identified in 1997 by two groups.^[8]^[9] The deduced amino acid sequences revealed that ALK was a novel receptor tyrosine kinase (RTK), having an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.^[8]^[9] While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the insulin receptor, its extracellular domain is unique among the RTK family in containing two MAM domains (meprin, A5 protein and receptor protein tyrosine phosphatase mu), an LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich region.^[9]^[10] Based on overall homology, ALK is closely related to the leukocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily.^[8]^[9] The human ALK gene encodes a protein 1,620 amino acids long with a molecular weight of 180 kDa.^[8]^[9]

Since the original discovery of the receptor in mammals, several orthologs of ALK have been identified: dAlk in the fruit fly (Drosophila melanogaster) in 2001,^[10] scd-2 in the nematode (Caenorhabditis elegans) in 2004,^[11] and DrAlk in the zebrafish (Danio rerio) in 2013.^[12]

The ligands of the human ALK/LTK receptors were identified in 2014:^[13]^[14]^[15] FAM150A (AUGβ) and FAM150B (AUGα), two small secreted peptides that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in Drosophila,^[16]^[17] and hesitation behaviour 1 (HEN-1) in C. elegans.^[18] No such ligands have been reported yet in zebrafish or other vertebrates.^[19]

Mechanism

Following binding of the ligand, the full-length receptor ALK dimerizes, changes conformation, and autoactivates its own kinase domain, which in turn phosphorylates other ALK receptors in trans on specific tyrosine amino acid residues. ALK phosphorylated residues serve as binding sites for the recruitment of several adaptor and other cellular proteins, such as GRB2,^[20] IRS1,^[20]^[21] Shc,^[20]^[22] Src,^[23] FRS2,^[22] PTPN11/Shp2,^[24] PLCγ,^[25]^[21] PI3K,^[26]^[21] and NF1.^[27] Other reported downstream ALK targets include FOXO3a,^[28] CDKN1B/p27kip,^[29] cyclin D2, NIPA,^[30]^[31] RAC1,^[32] CDC42,^[33] p130CAS,^[34] SHP1,^[35] and PIKFYVE.^[36]

Phosphorylated ALK activates multiple downstream signal transduction pathways, including MAPK-ERK, PI3K-AKT, PLCγ, CRKL-C3G, and JAK-STAT.^[37]^[19]

Function

The receptor ALK plays a pivotal role in cellular communication and in the normal development and function of the nervous system.^[6] This observation is based on the extensive expression of ALK messenger RNA (mRNA) throughout the nervous system during mouse embryogenesis.^[8]^[9]^[38] In vitro functional studies have demonstrated that ALK activation promotes neuronal differentiation of PC12^[39]^[40]^[41]^[22] or neuroblastoma cell lines.^[21]

ALK is critical for embryonic development in Drosophila. Flies lacking the receptor die due to failure of founder cell specification in embryonic visceral muscle.^[16]^[17]^[42] However, while ALK knockout mice exhibit defects in neurogenesis and testosterone production, they remain viable, suggesting that ALK is not critical to their developmental processes.^[43]^[44]^[45]

ALK regulates retinal axon targeting,^[46] growth and size,^[27]^[47] synapse development^[11] at the neuromuscular junction,^[48]^[49] behavioral responses to ethanol,^[50]^[51]^[52]^[53] and sleep.^[54] It restricts and constrains learning and long-term memory^[27]^[55]^[44] and small-molecule inhibitors of the ALK receptor can improve learning,^[27] long-term memory,^[55] and extend healthy lifespan.^[56] ALK is also a candidate thinness gene, as its genetic deletion leads to resistance to diet- and leptin-mutation-induced obesity.^[57]^{[N 1]}

Pathology

The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or with mutations of the actual DNA code for the gene itself.^[37]^[19]

Anaplastic large-cell lymphoma

The 2;5 chromosomal translocation is associated with approximately 60% of anaplastic large-cell lymphomas (ALCLs), type ALK-positive anaplastic large cell lymphoma and very rare cases of ALCL type primary cutaneous anaplastic large cell lymphoma. The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3. In rare cases, ALK is fused to other 5' fusion partners, such as TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9.^[58]

Adenocarcinoma of the lung

The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer (NSCLC). The vast majority of cases are adenocarcinomas.^[59] Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.^[60] The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry.^[59] Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.^{[citation needed]} ALK lung cancers are found in patients of all ages, although on average these patients tend to be younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.^[61]

Gene rearrangements and overexpression in other tumours

Familial cases of neuroblastoma^[62]
Inflammatory myofibroblastic tumor^[63]^[64]
Adult^[65]^[66] and pediatric^[67]^[68] renal cell carcinomas
Esophageal squamous cell carcinoma^[69]^[70]
Breast cancer,^[71] notably the inflammatory subtype^[72]
Colonic adenocarcinoma^[71]
Glioblastoma multiforme^[73]^[74]
Anaplastic thyroid cancer^[75]

ALK inhibitors

Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.^[76] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.

In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.^[77]^[78]^[79]

Ceritinib was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.^[80]
Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.

Notes and references

Notes

^ In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.

References

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External links

ALK+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ALK Correlations, Experiments, Publications and Clinical Trials
GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility
OMIM entries on ALK-Related Neuroblastoma Susceptibility
Human ALK genome location and ALK gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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@@ Line 1: / Line 1: @@
 {{Short description|Protein-coding gene in the species Homo sapiens}}
+{{cs1 config|name-list-style=vanc|display-authors=6}}
 {{Infobox_gene}}
 '''Anaplastic lymphoma kinase''' (ALK) also known as '''ALK tyrosine kinase receptor''' or '''CD246''' ([[cluster of differentiation]] 246) is an [[enzyme]] that in humans is encoded by the ''ALK'' [[gene]].<ref name="pmid8122112">{{cite journal | vauthors = Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT | title = Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma | journal = Science | volume = 263 | issue = 5151 | pages = 1281–1284 | date = March 1994 | pmid = 8122112 | doi = 10.1126/science.8122112 | bibcode = 1994Sci...263.1281M }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=238}}</ref>
@@ Line 6: / Line 7: @@
 Anaplastic lymphoma kinase (ALK) was originally discovered in 1994<ref name="pmid8122112" /><ref name=":13">{{cite journal | vauthors = Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S | title = Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3 | journal = Oncogene | volume = 9 | issue = 6 | pages = 1567–1574 | date = June 1994 | pmid = 8183550 }}</ref> in [[anaplastic large-cell lymphoma]] (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) [[chromosomal translocation]] that generates the [[fusion protein]] NPM-ALK, in which the [[kinase]] domain of ALK is fused to the amino-terminal part of the [[nucleophosmin]] (NPM) protein. [[Dimer (chemistry)|Dimer]]ization of NPM constitutively activates the ALK kinase domain.<ref name="pmid8122112" /><ref name=":13" />
-The full-length protein ALK was identified in 1997 by two groups.<ref name=":0">{{cite journal | vauthors = Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T | display-authors = 6 | title = Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system | journal = Oncogene | volume = 14 | issue = 4 | pages = 439–449 | date = January 1997 | pmid = 9053841 | doi = 10.1038/sj.onc.1200849 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP | title = ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) | journal = Oncogene | volume = 14 | issue = 18 | pages = 2175–2188 | date = May 1997 | pmid = 9174053 | doi = 10.1038/sj.onc.1201062 | doi-access = free }}</ref> The deduced [[amino acid]] sequences revealed that ALK was a novel [[receptor tyrosine kinase]] (RTK), having an [[extracellular domain|extracellular]] [[ligand-binding domain]], a [[transmembrane domain]], and an [[intracellular]] [[tyrosine kinase]] domain.<ref name=":0" /><ref name=":1" /> While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the [[insulin receptor]], its extracellular domain is unique among the RTK family in containing two [[MAM domain]]s ([[meprin]], A5 protein and [[receptor protein]] [[tyrosine phosphatase]] mu), an LDLa domain ([[low-density lipoprotein receptor]] class A) and a [[glycine]]-rich region.<ref name=":1" /><ref name=":2">{{cite journal | vauthors = Lorén CE, Scully A, Grabbe C, Edeen PT, Thomas J, McKeown M, Hunter T, Palmer RH | display-authors = 6 | title = Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo | journal = Genes to Cells | volume = 6 | issue = 6 | pages = 531–544 | date = June 2001 | pmid = 11442633 | pmc = 1975818 | doi = 10.1046/j.1365-2443.2001.00440.x }}</ref> Based on overall homology, ALK is closely related to the [[leukocyte receptor tyrosine kinase]] (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily.<ref name=":0" /><ref name=":1" /> The human ''ALK'' gene encodes a protein 1,620 amino acids long with a [[molecular weight]] of 180 [[kDa]].<ref name=":0" /><ref name=":1" />
+The full-length protein ALK was identified in 1997 by two groups.<ref name=":0">{{cite journal | vauthors = Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T | title = Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system | journal = Oncogene | volume = 14 | issue = 4 | pages = 439–449 | date = January 1997 | pmid = 9053841 | doi = 10.1038/sj.onc.1200849 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP | title = ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) | journal = Oncogene | volume = 14 | issue = 18 | pages = 2175–2188 | date = May 1997 | pmid = 9174053 | doi = 10.1038/sj.onc.1201062 | doi-access = free }}</ref> The deduced [[amino acid]] sequences revealed that ALK was a novel [[receptor tyrosine kinase]] (RTK), having an [[extracellular domain|extracellular]] [[ligand-binding domain]], a [[transmembrane domain]], and an [[intracellular]] [[tyrosine kinase]] domain.<ref name=":0" /><ref name=":1" /> While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the [[insulin receptor]], its extracellular domain is unique among the RTK family in containing two [[MAM domain]]s ([[meprin]], A5 protein and [[receptor protein]] [[tyrosine phosphatase]] mu), an LDLa domain ([[low-density lipoprotein receptor]] class A) and a [[glycine]]-rich region.<ref name=":1" /><ref name=":2">{{cite journal | vauthors = Lorén CE, Scully A, Grabbe C, Edeen PT, Thomas J, McKeown M, Hunter T, Palmer RH | title = Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo | journal = Genes to Cells | volume = 6 | issue = 6 | pages = 531–544 | date = June 2001 | pmid = 11442633 | pmc = 1975818 | doi = 10.1046/j.1365-2443.2001.00440.x }}</ref> Based on overall homology, ALK is closely related to the [[leukocyte receptor tyrosine kinase]] (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily.<ref name=":0" /><ref name=":1" /> The human ''ALK'' gene encodes a protein 1,620 amino acids long with a [[molecular weight]] of 180 [[kDa]].<ref name=":0" /><ref name=":1" />
 Since the original discovery of the receptor in mammals, several [[orthologs]] of ALK have been identified: dAlk in the [[Drosophilidae|fruit fly]] (''[[Drosophila melanogaster]]'') in 2001,<ref name=":2" /> scd-2 in the [[nematode]] (''[[Caenorhabditis elegans]]'') in 2004,<ref name="An SCF-like ubiquitin ligase comple">{{cite journal | vauthors = Liao EH, Hung W, Abrams B, Zhen M | title = An SCF-like ubiquitin ligase complex that controls presynaptic differentiation | journal = Nature | volume = 430 | issue = 6997 | pages = 345–350 | date = July 2004 | pmid = 15208641 | doi = 10.1038/nature02647 | s2cid = 4428538 | bibcode = 2004Natur.430..345L }}</ref> and DrAlk in the [[zebrafish]] (''[[Danio rerio]]'')  in 2013.<ref>{{cite journal | vauthors = Yao S, Cheng M, Zhang Q, Wasik M, Kelsh R, Winkler C | title = Anaplastic lymphoma kinase is required for neurogenesis in the developing central nervous system of zebrafish | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e63757 | date = May 2013 | pmid = 23667670 | pmc = 3648509 | doi = 10.1371/journal.pone.0063757 | doi-access = free | bibcode = 2013PLoSO...863757Y }}</ref>
-The [[ligands]] of the human ALK/LTK receptors were identified in 2014:<ref>{{cite journal | vauthors = Guan J, Umapathy G, Yamazaki Y, Wolfstetter G, Mendoza P, Pfeifer K, Mohammed A, Hugosson F, Zhang H, Hsu AW, Halenbeck R, Hallberg B, Palmer RH | display-authors = 6 | title = FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase | journal = eLife | volume = 4 | pages = e09811 | date = September 2015 | pmid = 26418745 | pmc = 4658194 | doi = 10.7554/eLife.09811 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Reshetnyak AV, Murray PB, Shi X, Mo ES, Mohanty J, Tome F, Bai H, Gunel M, Lax I, Schlessinger J | display-authors = 6 | title = Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 52 | pages = 15862–15867 | date = December 2015 | pmid = 26630010 | pmc = 4702955 | doi = 10.1073/pnas.1520099112 | doi-access = free | bibcode = 2015PNAS..11215862R }}</ref><ref>{{cite journal | vauthors = Zhang H, Pao LI, Zhou A, Brace AD, Halenbeck R, Hsu AW, Bray TL, Hestir K, Bosch E, Lee E, Wang G, Liu H, Wong BR, Kavanaugh WM, Williams LT | display-authors = 6 | title = Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 44 | pages = 15741–15745 | date = November 2014 | pmid = 25331893 | pmc = 4226105 | doi = 10.1073/pnas.1412009111 | doi-access = free | bibcode = 2014PNAS..11115741Z }}</ref> FAM150A (AUGβ) and FAM150B (AUGα), two small secreted [[peptide]]s that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in ''Drosophila'',<ref name=":3">{{cite journal | vauthors = Englund C, Lorén CE, Grabbe C, Varshney GK, Deleuil F, Hallberg B, Palmer RH | title = Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion | journal = Nature | volume = 425 | issue = 6957 | pages = 512–516 | date = October 2003 | pmid = 14523447 | doi = 10.1038/nature01950 | s2cid = 4425423 | bibcode = 2003Natur.425..512E }}</ref><ref name=":4">{{cite journal | vauthors = Lee HH, Norris A, Weiss JB, Frasch M | title = Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers | journal = Nature | volume = 425 | issue = 6957 | pages = 507–512 | date = October 2003 | pmid = 14523446 | doi = 10.1038/nature01916 | s2cid = 4424062 | bibcode = 2003Natur.425..507L }}</ref> and hesitation behaviour 1 (HEN-1) in ''C. elegans''.<ref>{{cite journal | vauthors = Reiner DJ, Ailion M, Thomas JH, Meyer BJ | title = C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling | journal = Current Biology | volume = 18 | issue = 15 | pages = 1101–1109 | date = August 2008 | pmid = 18674914 | pmc = 3489285 | doi = 10.1016/j.cub.2008.06.060 }}</ref> No such ligands have been reported yet in zebrafish or other [[vertebrate]]s.<ref name=":10" />
+The [[ligands]] of the human ALK/LTK receptors were identified in 2014:<ref>{{cite journal | vauthors = Guan J, Umapathy G, Yamazaki Y, Wolfstetter G, Mendoza P, Pfeifer K, Mohammed A, Hugosson F, Zhang H, Hsu AW, Halenbeck R, Hallberg B, Palmer RH | title = FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase | journal = eLife | volume = 4 | pages = e09811 | date = September 2015 | pmid = 26418745 | pmc = 4658194 | doi = 10.7554/eLife.09811 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Reshetnyak AV, Murray PB, Shi X, Mo ES, Mohanty J, Tome F, Bai H, Gunel M, Lax I, Schlessinger J | title = Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 52 | pages = 15862–15867 | date = December 2015 | pmid = 26630010 | pmc = 4702955 | doi = 10.1073/pnas.1520099112 | doi-access = free | bibcode = 2015PNAS..11215862R }}</ref><ref>{{cite journal | vauthors = Zhang H, Pao LI, Zhou A, Brace AD, Halenbeck R, Hsu AW, Bray TL, Hestir K, Bosch E, Lee E, Wang G, Liu H, Wong BR, Kavanaugh WM, Williams LT | title = Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 44 | pages = 15741–15745 | date = November 2014 | pmid = 25331893 | pmc = 4226105 | doi = 10.1073/pnas.1412009111 | doi-access = free | bibcode = 2014PNAS..11115741Z }}</ref> FAM150A (AUGβ) and FAM150B (AUGα), two small secreted [[peptide]]s that strongly activate ALK signaling. In invertebrates, ALK-activating ligands are Jelly belly (Jeb) in ''Drosophila'',<ref name=":3">{{cite journal | vauthors = Englund C, Lorén CE, Grabbe C, Varshney GK, Deleuil F, Hallberg B, Palmer RH | title = Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion | journal = Nature | volume = 425 | issue = 6957 | pages = 512–516 | date = October 2003 | pmid = 14523447 | doi = 10.1038/nature01950 | s2cid = 4425423 | bibcode = 2003Natur.425..512E }}</ref><ref name=":4">{{cite journal | vauthors = Lee HH, Norris A, Weiss JB, Frasch M | title = Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers | journal = Nature | volume = 425 | issue = 6957 | pages = 507–512 | date = October 2003 | pmid = 14523446 | doi = 10.1038/nature01916 | s2cid = 4424062 | bibcode = 2003Natur.425..507L }}</ref> and hesitation behaviour 1 (HEN-1) in ''C. elegans''.<ref>{{cite journal | vauthors = Reiner DJ, Ailion M, Thomas JH, Meyer BJ | title = C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling | journal = Current Biology | volume = 18 | issue = 15 | pages = 1101–1109 | date = August 2008 | pmid = 18674914 | pmc = 3489285 | doi = 10.1016/j.cub.2008.06.060 | bibcode = 2008CBio...18.1101R }}</ref> No such ligands have been reported yet in zebrafish or other [[vertebrate]]s.<ref name=":10" />
 == Mechanism ==
-Following binding of the ligand, the full-length receptor ALK [[dimerizes]], [[Conformational change|changes conformation]], and [[Autophosphorylation|autoactivates]] its own [[kinase]] domain, which in turn [[phosphorylates]] other ALK receptors [[Trans-acting|in ''trans'']] on specific [[tyrosine]] amino acid residues. ALK phosphorylated residues serve as [[binding site]]s for the recruitment of several [[Adaptor molecule|adaptor]] and other cellular proteins, such as [[GRB2]],<ref name=":5">{{cite journal | vauthors = Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T | title = Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 9 | pages = 4181–4186 | date = April 1996 | pmid = 8633037 | pmc = 39508 | doi = 10.1073/pnas.93.9.4181 | doi-access = free | bibcode = 1996PNAS...93.4181F }}</ref> [[IRS1]],<ref name=":5" /><ref name=":6">{{cite journal | vauthors = Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T | title = ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth | journal = Journal of Cell Science | volume = 117 | issue = Pt 15 | pages = 3319–3329 | date = July 2004 | pmid = 15226403 | doi = 10.1242/jcs.01183 | doi-access = free }}</ref> [[SHC1|Shc]],<ref name=":5" /><ref name=":7">{{cite journal | vauthors = Degoutin J, Vigny M, Gouzi JY | title = ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation | journal = FEBS Letters | volume = 581 | issue = 4 | pages = 727–734 | date = February 2007 | pmid = 17274988 | doi = 10.1016/j.febslet.2007.01.039 | s2cid = 40978851 | doi-access = free }}</ref> [[Src family kinase|Src]],<ref>{{cite journal | vauthors = Cussac D, Greenland C, Roche S, Bai RY, Duyster J, Morris SW, Delsol G, Allouche M, Payrastre B | display-authors = 6 | title = Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity | journal = Blood | volume = 103 | issue = 4 | pages = 1464–1471 | date = February 2004 | pmid = 14563642 | doi = 10.1182/blood-2003-04-1038 | doi-access = free }}</ref> [[FRS2]],<ref name=":7" /> [[PTPN11|PTPN11/Shp2]],<ref>{{cite journal | vauthors = Voena C, Conte C, Ambrogio C, Boeri Erba E, Boccalatte F, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R | display-authors = 6 | title = The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4278–4286 | date = May 2007 | pmid = 17483340 | doi = 10.1158/0008-5472.CAN-06-4350 | doi-access = free }}</ref> [[PLCγ]],<ref>{{cite journal | vauthors = Bai RY, Dieter P, Peschel C, Morris SW, Duyster J | title = Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 6951–6961 | date = December 1998 | pmid = 9819383 | pmc = 109278 | doi = 10.1128/mcb.18.12.6951 }}</ref><ref name=":6" /> [[PI3K]],<ref>{{cite journal | vauthors = Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J | title = Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway | journal = Blood | volume = 96 | issue = 13 | pages = 4319–4327 | date = December 2000 | pmid = 11110708 | doi = 10.1182/blood.v96.13.4319.h8004319_4319_4327 }}</ref><ref name=":6" /> and [[Nf1|NF1]].<ref name=":8">{{cite journal | vauthors = Gouzi JY, Moressis A, Walker JA, Apostolopoulou AA, Palmer RH, Bernards A, Skoulakis EM | title = The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning | journal = PLOS Genetics | volume = 7 | issue = 9 | pages = e1002281 | date = September 2011 | pmid = 21949657 | pmc = 3174217 | doi = 10.1371/journal.pgen.1002281 | doi-access = free }}</ref> Other reported downstream ALK targets include [[FOXO3]]a,<ref>{{cite journal | vauthors = Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW | title = NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a | journal = Blood | volume = 103 | issue = 12 | pages = 4622–4629 | date = June 2004 | pmid = 14962911 | doi = 10.1182/blood-2003-03-0820 | doi-access = free }}</ref> [[CDKN1B|CDKN1B/p27kip]],<ref>{{cite journal | vauthors = Rassidakis GZ, Feretzaki M, Atwell C, Grammatikakis I, Lin Q, Lai R, Claret FX, Medeiros LJ, Amin HM | display-authors = 6 | title = Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma | journal = Blood | volume = 105 | issue = 2 | pages = 827–829 | date = January 2005 | pmid = 15374880 | pmc = 1382060 | doi = 10.1182/blood-2004-06-2125 }}</ref> [[cyclin D2]], [[E3 ligase|NIPA]],<ref>{{cite journal | vauthors = Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J | display-authors = 6 | title = Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30028–30036 | date = August 2003 | pmid = 12748172 | doi = 10.1074/jbc.M300883200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J | display-authors = 6 | title = NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | journal = Cell | volume = 122 | issue = 1 | pages = 45–57 | date = July 2005 | pmid = 16009132 | doi = 10.1016/j.cell.2005.04.034 | s2cid = 16122567 | doi-access = free }}</ref> [[RAC1]],<ref>{{cite journal | vauthors = Colomba A, Courilleau D, Ramel D, Billadeau DD, Espinos E, Delsol G, Payrastre B, Gaits-Iacovoni F | display-authors = 6 | title = Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas | journal = Oncogene | volume = 27 | issue = 19 | pages = 2728–2736 | date = April 2008 | pmid = 17998938 | doi = 10.1038/sj.onc.1210921 | doi-access = free }}</ref> [[CDC42]],<ref>{{cite journal | vauthors = Ambrogio C, Voena C, Manazza AD, Martinengo C, Costa C, Kirchhausen T, Hirsch E, Inghirami G, Chiarle R | display-authors = 6 | title = The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation | journal = Cancer Research | volume = 68 | issue = 21 | pages = 8899–8907 | date = November 2008 | pmid = 18974134 | pmc = 2596920 | doi = 10.1158/0008-5472.CAN-08-2568 }}</ref> p130CAS,<ref>{{cite journal | vauthors = Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R | display-authors = 6 | title = p130Cas mediates the transforming properties of the anaplastic lymphoma kinase | journal = Blood | volume = 106 | issue = 12 | pages = 3907–3916 | date = December 2005 | pmid = 16105984 | pmc = 1895100 | doi = 10.1182/blood-2005-03-1204 }}</ref> [[SHP1]],<ref>{{cite journal | vauthors = Hegazy SA, Wang P, Anand M, Ingham RJ, Gelebart P, Lai R | title = The tyrosine 343 residue of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions | journal = The Journal of Biological Chemistry | volume = 285 | issue = 26 | pages = 19813–19820 | date = June 2010 | pmid = 20424160 | pmc = 2888392 | doi = 10.1074/jbc.M110.121988 | doi-access = free }}</ref> and [[PIKFYVE]].<ref>{{cite journal | vauthors = Dupuis-Coronas S, Lagarrigue F, Ramel D, Chicanne G, Saland E, Gaits-Iacovoni F, Payrastre B, Tronchère H | display-authors = 6 | title = The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness | journal = The Journal of Biological Chemistry | volume = 286 | issue = 37 | pages = 32105–32114 | date = September 2011 | pmid = 21737449 | pmc = 3173219 | doi = 10.1074/jbc.M111.227512 | doi-access = free }}</ref>
+Following binding of the ligand, the full-length receptor ALK [[dimerizes]], [[Conformational change|changes conformation]], and [[Autophosphorylation|autoactivates]] its own [[kinase]] domain, which in turn [[phosphorylates]] other ALK receptors [[Trans-acting|in ''trans'']] on specific [[tyrosine]] amino acid residues. ALK phosphorylated residues serve as [[binding site]]s for the recruitment of several [[Adaptor molecule|adaptor]] and other cellular proteins, such as [[GRB2]],<ref name=":5">{{cite journal | vauthors = Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T | title = Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 9 | pages = 4181–4186 | date = April 1996 | pmid = 8633037 | pmc = 39508 | doi = 10.1073/pnas.93.9.4181 | doi-access = free | bibcode = 1996PNAS...93.4181F }}</ref> [[IRS1]],<ref name=":5" /><ref name=":6">{{cite journal | vauthors = Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T | title = ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth | journal = Journal of Cell Science | volume = 117 | issue = Pt 15 | pages = 3319–3329 | date = July 2004 | pmid = 15226403 | doi = 10.1242/jcs.01183 | doi-access = free }}</ref> [[SHC1|Shc]],<ref name=":5" /><ref name=":7">{{cite journal | vauthors = Degoutin J, Vigny M, Gouzi JY | title = ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation | journal = FEBS Letters | volume = 581 | issue = 4 | pages = 727–734 | date = February 2007 | pmid = 17274988 | doi = 10.1016/j.febslet.2007.01.039 | s2cid = 40978851 | doi-access = free }}</ref> [[Src family kinase|Src]],<ref>{{cite journal | vauthors = Cussac D, Greenland C, Roche S, Bai RY, Duyster J, Morris SW, Delsol G, Allouche M, Payrastre B | title = Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity | journal = Blood | volume = 103 | issue = 4 | pages = 1464–1471 | date = February 2004 | pmid = 14563642 | doi = 10.1182/blood-2003-04-1038 | doi-access = free }}</ref> [[FRS2]],<ref name=":7" /> [[PTPN11|PTPN11/Shp2]],<ref>{{cite journal | vauthors = Voena C, Conte C, Ambrogio C, Boeri Erba E, Boccalatte F, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R | title = The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4278–4286 | date = May 2007 | pmid = 17483340 | doi = 10.1158/0008-5472.CAN-06-4350 | doi-access = free }}</ref> [[PLCγ]],<ref>{{cite journal | vauthors = Bai RY, Dieter P, Peschel C, Morris SW, Duyster J | title = Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 6951–6961 | date = December 1998 | pmid = 9819383 | pmc = 109278 | doi = 10.1128/mcb.18.12.6951 }}</ref><ref name=":6" /> [[PI3K]],<ref>{{cite journal | vauthors = Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J | title = Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway | journal = Blood | volume = 96 | issue = 13 | pages = 4319–4327 | date = December 2000 | pmid = 11110708 | doi = 10.1182/blood.V96.13.4319 }}</ref><ref name=":6" /> and [[Nf1|NF1]].<ref name=":8">{{cite journal | vauthors = Gouzi JY, Moressis A, Walker JA, Apostolopoulou AA, Palmer RH, Bernards A, Skoulakis EM | title = The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning | journal = PLOS Genetics | volume = 7 | issue = 9 | pages = e1002281 | date = September 2011 | pmid = 21949657 | pmc = 3174217 | doi = 10.1371/journal.pgen.1002281 | doi-access = free }}</ref> Other reported downstream ALK targets include [[FOXO3]]a,<ref>{{cite journal | vauthors = Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW | title = NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a | journal = Blood | volume = 103 | issue = 12 | pages = 4622–4629 | date = June 2004 | pmid = 14962911 | doi = 10.1182/blood-2003-03-0820 | doi-access = free }}</ref> [[CDKN1B|CDKN1B/p27kip]],<ref>{{cite journal | vauthors = Rassidakis GZ, Feretzaki M, Atwell C, Grammatikakis I, Lin Q, Lai R, Claret FX, Medeiros LJ, Amin HM | title = Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma | journal = Blood | volume = 105 | issue = 2 | pages = 827–829 | date = January 2005 | pmid = 15374880 | pmc = 1382060 | doi = 10.1182/blood-2004-06-2125 }}</ref> [[cyclin D2]], [[E3 ligase|NIPA]],<ref>{{cite journal | vauthors = Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C, Morris SW, Peschel C, Duyster J | title = Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30028–30036 | date = August 2003 | pmid = 12748172 | doi = 10.1074/jbc.M300883200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bassermann F, von Klitzing C, Münch S, Bai RY, Kawaguchi H, Morris SW, Peschel C, Duyster J | title = NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry | journal = Cell | volume = 122 | issue = 1 | pages = 45–57 | date = July 2005 | pmid = 16009132 | doi = 10.1016/j.cell.2005.04.034 | s2cid = 16122567 | doi-access = free }}</ref> [[RAC1]],<ref>{{cite journal | vauthors = Colomba A, Courilleau D, Ramel D, Billadeau DD, Espinos E, Delsol G, Payrastre B, Gaits-Iacovoni F | title = Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas | journal = Oncogene | volume = 27 | issue = 19 | pages = 2728–2736 | date = April 2008 | pmid = 17998938 | doi = 10.1038/sj.onc.1210921 | doi-access = free }}</ref> [[CDC42]],<ref>{{cite journal | vauthors = Ambrogio C, Voena C, Manazza AD, Martinengo C, Costa C, Kirchhausen T, Hirsch E, Inghirami G, Chiarle R | title = The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation | journal = Cancer Research | volume = 68 | issue = 21 | pages = 8899–8907 | date = November 2008 | pmid = 18974134 | pmc = 2596920 | doi = 10.1158/0008-5472.CAN-08-2568 }}</ref> p130CAS,<ref>{{cite journal | vauthors = Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R | title = p130Cas mediates the transforming properties of the anaplastic lymphoma kinase | journal = Blood | volume = 106 | issue = 12 | pages = 3907–3916 | date = December 2005 | pmid = 16105984 | pmc = 1895100 | doi = 10.1182/blood-2005-03-1204 }}</ref> [[SHP1]],<ref>{{cite journal | vauthors = Hegazy SA, Wang P, Anand M, Ingham RJ, Gelebart P, Lai R | title = The tyrosine 343 residue of nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) is important for its interaction with SHP1, a cytoplasmic tyrosine phosphatase with tumor suppressor functions | journal = The Journal of Biological Chemistry | volume = 285 | issue = 26 | pages = 19813–19820 | date = June 2010 | pmid = 20424160 | pmc = 2888392 | doi = 10.1074/jbc.M110.121988 | doi-access = free }}</ref> and [[PIKFYVE]].<ref>{{cite journal | vauthors = Dupuis-Coronas S, Lagarrigue F, Ramel D, Chicanne G, Saland E, Gaits-Iacovoni F, Payrastre B, Tronchère H | title = The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness | journal = The Journal of Biological Chemistry | volume = 286 | issue = 37 | pages = 32105–32114 | date = September 2011 | pmid = 21737449 | pmc = 3173219 | doi = 10.1074/jbc.M111.227512 | doi-access = free }}</ref>
 Phosphorylated ALK activates multiple downstream [[signal transduction]] pathways, including [[MAPK/ERK pathway|MAPK-ERK]], [[PI3K/AKT/mTOR pathway|PI3K-AKT]], [[Phospholipase C|PLCγ]], [[CRKL|CRKL-C3G]], and [[JAK-STAT signaling pathway|JAK-STAT]].<ref name=":9">{{cite journal | vauthors = Palmer RH, Vernersson E, Grabbe C, Hallberg B | title = Anaplastic lymphoma kinase: signalling in development and disease | journal = The Biochemical Journal | volume = 420 | issue = 3 | pages = 345–361 | date = May 2009 | pmid = 19459784 | pmc = 2708929 | doi = 10.1042/BJ20090387 }}</ref><ref name=":10">{{cite journal | vauthors = Hallberg B, Palmer RH | title = Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology | journal = Nature Reviews. Cancer | volume = 13 | issue = 10 | pages = 685–700 | date = October 2013 | pmid = 24060861 | doi = 10.1038/nrc3580 | s2cid = 21345361 }}</ref>
 == Function ==
-The receptor ALK plays a pivotal role in [[Cellular communication (biology)|cellular communication]] and in the normal [[Nervous system|development and function of the nervous system]].<ref name="entrez" /> This observation is based on the extensive expression of ALK [[messenger RNA]] (mRNA) throughout the nervous system during mouse [[Embryonic development|embryogenesis]].<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Vernersson E, Khoo NK, Henriksson ML, Roos G, Palmer RH, Hallberg B | title = Characterization of the expression of the ALK receptor tyrosine kinase in mice | journal = Gene Expression Patterns | volume = 6 | issue = 5 | pages = 448–461 | date = June 2006 | pmid = 16458083 | doi = 10.1016/j.modgep.2005.11.006 }}</ref> ''[[In vitro]]'' functional studies have demonstrated that ALK activation promotes [[neuron]]al [[Cellular differentiation|differentiation]] of [[PC12 cell line|PC12]]<ref>{{cite journal | vauthors = Souttou B, Carvalho NB, Raulais D, Vigny M | title = Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9526–9531 | date = March 2001 | pmid = 11121404 | doi = 10.1074/jbc.M007333200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Moog-Lutz C, Degoutin J, Gouzi JY, Frobert Y, Brunet-de Carvalho N, Bureau J, Créminon C, Vigny M | display-authors = 6 | title = Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 26039–26048 | date = July 2005 | pmid = 15886198 | doi = 10.1074/jbc.M501972200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gouzi JY, Moog-Lutz C, Vigny M, Brunet-de Carvalho N | title = Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells | journal = Journal of Cell Science | volume = 118 | issue = Pt 24 | pages = 5811–5823 | date = December 2005 | pmid = 16317043 | doi = 10.1242/jcs.02695 | doi-access = free }}</ref><ref name=":7" /> or [[neuroblastoma]] cell lines.<ref name=":6" />
+The receptor ALK plays a pivotal role in [[Cellular communication (biology)|cellular communication]] and in the normal [[Nervous system|development and function of the nervous system]].<ref name="entrez" /> This observation is based on the extensive expression of ALK [[messenger RNA]] (mRNA) throughout the nervous system during mouse [[Embryonic development|embryogenesis]].<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Vernersson E, Khoo NK, Henriksson ML, Roos G, Palmer RH, Hallberg B | title = Characterization of the expression of the ALK receptor tyrosine kinase in mice | journal = Gene Expression Patterns | volume = 6 | issue = 5 | pages = 448–461 | date = June 2006 | pmid = 16458083 | doi = 10.1016/j.modgep.2005.11.006 }}</ref> ''[[In vitro]]'' functional studies have demonstrated that ALK activation promotes [[neuron]]al [[Cellular differentiation|differentiation]] of [[PC12 cell line|PC12]]<ref>{{cite journal | vauthors = Souttou B, Carvalho NB, Raulais D, Vigny M | title = Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9526–9531 | date = March 2001 | pmid = 11121404 | doi = 10.1074/jbc.M007333200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Moog-Lutz C, Degoutin J, Gouzi JY, Frobert Y, Brunet-de Carvalho N, Bureau J, Créminon C, Vigny M | title = Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 26039–26048 | date = July 2005 | pmid = 15886198 | doi = 10.1074/jbc.M501972200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gouzi JY, Moog-Lutz C, Vigny M, Brunet-de Carvalho N | title = Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells | journal = Journal of Cell Science | volume = 118 | issue = Pt 24 | pages = 5811–5823 | date = December 2005 | pmid = 16317043 | doi = 10.1242/jcs.02695 | doi-access = free }}</ref><ref name=":7" /> or [[neuroblastoma]] cell lines.<ref name=":6" />
-ALK is critical for [[embryonic development]] in ''[[Drosophila]]''. Flies lacking the receptor die due to failure of founder cell specification in embryonic visceral muscle.<ref name=":3" /><ref name=":4" /><ref>{{cite journal | vauthors = Stute C, Schimmelpfeng K, Renkawitz-Pohl R, Palmer RH, Holz A | title = Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways(mili(Alk)) as receptor for Jeb signalling | journal = Development | volume = 131 | issue = 4 | pages = 743–754 | date = February 2004 | pmid = 14757637 | doi = 10.1242/dev.00972 | doi-access = free }}</ref> However, while ALK [[Knockout mouse|knockout mice]] exhibit defects in [[neurogenesis]] and [[testosterone]] production, they remain viable, suggesting that ALK is not critical to their developmental processes.<ref>{{cite journal | vauthors = Bilsland JG, Wheeldon A, Mead A, Znamenskiy P, Almond S, Waters KA, Thakur M, Beaumont V, Bonnert TP, Heavens R, Whiting P, McAllister G, Munoz-Sanjuan I | display-authors = 6 | title = Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications | journal = Neuropsychopharmacology | volume = 33 | issue = 3 | pages = 685–700 | date = February 2008 | pmid = 17487225 | doi = 10.1038/sj.npp.1301446 | doi-access = free }}</ref><ref name=":11">{{cite journal | vauthors = Weiss JB, Xue C, Benice T, Xue L, Morris SW, Raber J | title = Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis | journal = Pharmacology, Biochemistry, and Behavior | volume = 100 | issue = 3 | pages = 566–574 | date = January 2012 | pmid = 22079349 | doi = 10.1016/j.pbb.2011.10.024 | s2cid = 2386055 }}</ref><ref>{{cite journal | vauthors = Witek B, El Wakil A, Nord C, Ahlgren U, Eriksson M, Vernersson-Lindahl E, Helland Å, Alexeyev OA, Hallberg B, Palmer RH | display-authors = 6 | title = Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism | journal = PLOS ONE | volume = 10 | issue = 5 | pages = e0123542 | date = May 2015 | pmid = 25955180 | pmc = 4425494 | doi = 10.1371/journal.pone.0123542 | doi-access = free | bibcode = 2015PLoSO..1023542W }}</ref>
+ALK is critical for [[embryonic development]] in ''[[Drosophila]]''. Flies lacking the receptor die due to failure of founder cell specification in embryonic visceral muscle.<ref name=":3" /><ref name=":4" /><ref>{{cite journal | vauthors = Stute C, Schimmelpfeng K, Renkawitz-Pohl R, Palmer RH, Holz A | title = Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways(mili(Alk)) as receptor for Jeb signalling | journal = Development | volume = 131 | issue = 4 | pages = 743–754 | date = February 2004 | pmid = 14757637 | doi = 10.1242/dev.00972 | doi-access = free }}</ref> However, while ALK [[Knockout mouse|knockout mice]] exhibit defects in [[neurogenesis]] and [[testosterone]] production, they remain viable, suggesting that ALK is not critical to their developmental processes.<ref>{{cite journal | vauthors = Bilsland JG, Wheeldon A, Mead A, Znamenskiy P, Almond S, Waters KA, Thakur M, Beaumont V, Bonnert TP, Heavens R, Whiting P, McAllister G, Munoz-Sanjuan I | title = Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications | journal = Neuropsychopharmacology | volume = 33 | issue = 3 | pages = 685–700 | date = February 2008 | pmid = 17487225 | doi = 10.1038/sj.npp.1301446 | doi-access = free }}</ref><ref name=":11">{{cite journal | vauthors = Weiss JB, Xue C, Benice T, Xue L, Morris SW, Raber J | title = Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis | journal = Pharmacology, Biochemistry, and Behavior | volume = 100 | issue = 3 | pages = 566–574 | date = January 2012 | pmid = 22079349 | doi = 10.1016/j.pbb.2011.10.024 | s2cid = 2386055 }}</ref><ref>{{cite journal | vauthors = Witek B, El Wakil A, Nord C, Ahlgren U, Eriksson M, Vernersson-Lindahl E, Helland Å, Alexeyev OA, Hallberg B, Palmer RH | title = Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism | journal = PLOS ONE | volume = 10 | issue = 5 | pages = e0123542 | date = May 2015 | pmid = 25955180 | pmc = 4425494 | doi = 10.1371/journal.pone.0123542 | doi-access = free | bibcode = 2015PLoSO..1023542W }}</ref>
-ALK regulates [[retina]]l [[Axon guidance|axon targeting]],<ref>{{cite journal | vauthors = Bazigou E, Apitz H, Johansson J, Lorén CE, Hirst EM, Chen PL, Palmer RH, Salecker I | display-authors = 6 | title = Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila | journal = Cell | volume = 128 | issue = 5 | pages = 961–975 | date = March 2007 | pmid = 17350579 | doi = 10.1016/j.cell.2007.02.024 | s2cid = 10341647 | doi-access = free }}</ref> growth and size,<ref name=":8" /><ref>{{cite journal | vauthors = Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC, Gould AP | title = Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila | journal = Cell | volume = 146 | issue = 3 | pages = 435–447 | date = August 2011 | pmid = 21816278 | doi = 10.1016/j.cell.2011.06.040 | s2cid = 4287148 | doi-access = free }}</ref> [[synapse]] development<ref name="An SCF-like ubiquitin ligase comple"/> at the [[neuromuscular junction]],<ref>{{cite journal | vauthors = Rohrbough J, Broadie K | title = Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap | journal = Development | volume = 137 | issue = 20 | pages = 3523–3533 | date = October 2010 | pmid = 20876658 | pmc = 2947762 | doi = 10.1242/dev.047878 }}</ref><ref>{{cite journal | vauthors = Rohrbough J, Kent KS, Broadie K, Weiss JB | title = Jelly Belly trans-synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture | journal = Developmental Neurobiology | volume = 73 | issue = 3 | pages = 189–208 | date = March 2013 | pmid = 22949158 | pmc = 3565053 | doi = 10.1002/dneu.22056 }}</ref> behavioral responses to [[ethanol]],<ref>{{cite journal | vauthors = Lasek AW, Lim J, Kliethermes CL, Berger KH, Joslyn G, Brush G, Xue L, Robertson M, Moore MS, Vranizan K, Morris SW, Schuckit MA, White RL, Heberlein U | display-authors = 6 | title = An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol | journal = PLOS ONE | volume = 6 | issue = 7 | pages = e22636 | date = Jul 2011 | pmid = 21799923 | pmc = 3142173 | doi = 10.1371/journal.pone.0022636 | doi-access = free | bibcode = 2011PLoSO...622636L }}</ref><ref>{{cite journal | vauthors = Schweitzer P, Cates-Gatto C, Varodayan FP, Nadav T, Roberto M, Lasek AW, Roberts AJ | title = Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice | journal = Neuropharmacology | volume = 107 | pages = 1–8 | date = August 2016 | pmid = 26946429 | pmc = 4912883 | doi = 10.1016/j.neuropharm.2016.03.003 }}</ref><ref>{{cite journal | vauthors = Dutton JW, Chen H, You C, Brodie MS, Lasek AW | title = Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area | journal = Addiction Biology | volume = 22 | issue = 3 | pages = 665–678 | date = May 2017 | pmid = 26752591 | pmc = 4940304 | doi = 10.1111/adb.12358 }}</ref><ref>{{cite journal | vauthors = Mangieri RA, Maier EY, Buske TR, Lasek AW, Morrisett RA | title = Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell | journal = Frontiers in Pharmacology | volume = 8 | pages = 533 | date = Aug 2017 | pmid = 28860990 | pmc = 5559467 | doi = 10.3389/fphar.2017.00533 | doi-access = free }}</ref> and [[sleep]].<ref>{{cite journal | vauthors = Bai L, Sehgal A | title = Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep | journal = PLOS Genetics | volume = 11 | issue = 11 | pages = e1005611 | date = November 2015 | pmid = 26536237 | pmc = 4633181 | doi = 10.1371/journal.pgen.1005611 | doi-access = free }}</ref> It restricts and constrains [[learning]] and [[long-term memory]]<ref name=":8" /><ref name=":12">{{cite journal | vauthors = Gouzi JY, Bouraimi M, Roussou IG, Moressis A, Skoulakis EM | title = The ''Drosophila'' Receptor Tyrosine Kinase Alk Constrains Long-Term Memory Formation | journal = The Journal of Neuroscience | volume = 38 | issue = 35 | pages = 7701–7712 | date = August 2018 | pmid = 30030398 | pmc = 6705970 | doi = 10.1523/JNEUROSCI.0784-18.2018 }}</ref><ref name=":11" /> and [[ALK inhibitor|small-molecule inhibitor]]s of the ALK receptor can improve learning,<ref name=":8" /> long-term memory,<ref name=":12" /> and extend healthy [[Life expectancy|lifespan]].<ref>{{cite journal | vauthors = Woodling NS, Aleyakpo B, Dyson MC, Minkley LJ, Rajasingam A, Dobson AJ, Leung KH, Pomposova S, Fuentealba M, Alic N, Partridge L | display-authors = 6 | title = The neuronal receptor tyrosine kinase Alk is a target for longevity | journal = Aging Cell | volume = 19 | issue = 5 | pages = e13137 | date = May 2020 | pmid = 32291952 | pmc = 7253064 | doi = 10.1111/acel.13137 | doi-access = free }}</ref> ALK is also a candidate [[thinness]] gene, as its genetic deletion leads to resistance to diet- and [[leptin]]-mutation-induced [[obesity]].<ref>{{cite journal | vauthors = Orthofer M, Valsesia A, Mägi R, Wang QP, Kaczanowska J, Kozieradzki I, Leopoldi A, Cikes D, Zopf LM, Tretiakov EO, Demetz E, Hilbe R, Boehm A, Ticevic M, Nõukas M, Jais A, Spirk K, Clark T, Amann S, Lepamets M, Neumayr C, Arnold C, Dou Z, Kuhn V, Novatchkova M, Cronin SJ, Tietge UJ, Müller S, Pospisilik JA, Nagy V, Hui CC, Lazovic J, Esterbauer H, Hagelkruys A, Tancevski I, Kiefer FW, Harkany T, Haubensak W, Neely GG, Metspalu A, Hager J, Gheldof N, Penninger JM | display-authors = 6 | title = Identification of ALK in Thinness | journal = Cell | volume = 181 | issue = 6 | pages = 1246–1262.e22 | date = June 2020 | pmid = 32442405 | doi = 10.1016/j.cell.2020.04.034 | s2cid = 218762956 | doi-access = free }}</ref><ref group="N">In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.</ref>
+ALK regulates [[retina]]l [[Axon guidance|axon targeting]],<ref>{{cite journal | vauthors = Bazigou E, Apitz H, Johansson J, Lorén CE, Hirst EM, Chen PL, Palmer RH, Salecker I | title = Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila | journal = Cell | volume = 128 | issue = 5 | pages = 961–975 | date = March 2007 | pmid = 17350579 | doi = 10.1016/j.cell.2007.02.024 | s2cid = 10341647 | doi-access = free }}</ref> growth and size,<ref name=":8" /><ref>{{cite journal | vauthors = Cheng LY, Bailey AP, Leevers SJ, Ragan TJ, Driscoll PC, Gould AP | title = Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila | journal = Cell | volume = 146 | issue = 3 | pages = 435–447 | date = August 2011 | pmid = 21816278 | doi = 10.1016/j.cell.2011.06.040 | s2cid = 4287148 | doi-access = free }}</ref> [[synapse]] development<ref name="An SCF-like ubiquitin ligase comple"/> at the [[neuromuscular junction]],<ref>{{cite journal | vauthors = Rohrbough J, Broadie K | title = Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap | journal = Development | volume = 137 | issue = 20 | pages = 3523–3533 | date = October 2010 | pmid = 20876658 | pmc = 2947762 | doi = 10.1242/dev.047878 }}</ref><ref>{{cite journal | vauthors = Rohrbough J, Kent KS, Broadie K, Weiss JB | title = Jelly Belly trans-synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture | journal = Developmental Neurobiology | volume = 73 | issue = 3 | pages = 189–208 | date = March 2013 | pmid = 22949158 | pmc = 3565053 | doi = 10.1002/dneu.22056 }}</ref> behavioral responses to [[ethanol]],<ref>{{cite journal | vauthors = Lasek AW, Lim J, Kliethermes CL, Berger KH, Joslyn G, Brush G, Xue L, Robertson M, Moore MS, Vranizan K, Morris SW, Schuckit MA, White RL, Heberlein U | title = An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol | journal = PLOS ONE | volume = 6 | issue = 7 | pages = e22636 | date = Jul 2011 | pmid = 21799923 | pmc = 3142173 | doi = 10.1371/journal.pone.0022636 | doi-access = free | bibcode = 2011PLoSO...622636L }}</ref><ref>{{cite journal | vauthors = Schweitzer P, Cates-Gatto C, Varodayan FP, Nadav T, Roberto M, Lasek AW, Roberts AJ | title = Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice | journal = Neuropharmacology | volume = 107 | pages = 1–8 | date = August 2016 | pmid = 26946429 | pmc = 4912883 | doi = 10.1016/j.neuropharm.2016.03.003 }}</ref><ref>{{cite journal | vauthors = Dutton JW, Chen H, You C, Brodie MS, Lasek AW | title = Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area | journal = Addiction Biology | volume = 22 | issue = 3 | pages = 665–678 | date = May 2017 | pmid = 26752591 | pmc = 4940304 | doi = 10.1111/adb.12358 }}</ref><ref>{{cite journal | vauthors = Mangieri RA, Maier EY, Buske TR, Lasek AW, Morrisett RA | title = Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell | journal = Frontiers in Pharmacology | volume = 8 | pages = 533 | date = Aug 2017 | pmid = 28860990 | pmc = 5559467 | doi = 10.3389/fphar.2017.00533 | doi-access = free }}</ref> and [[sleep]].<ref>{{cite journal | vauthors = Bai L, Sehgal A | title = Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep | journal = PLOS Genetics | volume = 11 | issue = 11 | pages = e1005611 | date = November 2015 | pmid = 26536237 | pmc = 4633181 | doi = 10.1371/journal.pgen.1005611 | doi-access = free }}</ref> It restricts and constrains [[learning]] and [[long-term memory]]<ref name=":8" /><ref name=":12">{{cite journal | vauthors = Gouzi JY, Bouraimi M, Roussou IG, Moressis A, Skoulakis EM | title = The ''Drosophila'' Receptor Tyrosine Kinase Alk Constrains Long-Term Memory Formation | journal = The Journal of Neuroscience | volume = 38 | issue = 35 | pages = 7701–7712 | date = August 2018 | pmid = 30030398 | pmc = 6705970 | doi = 10.1523/JNEUROSCI.0784-18.2018 }}</ref><ref name=":11" /> and [[ALK inhibitor|small-molecule inhibitor]]s of the ALK receptor can improve learning,<ref name=":8" /> long-term memory,<ref name=":12" /> and extend healthy [[Life expectancy|lifespan]].<ref>{{cite journal | vauthors = Woodling NS, Aleyakpo B, Dyson MC, Minkley LJ, Rajasingam A, Dobson AJ, Leung KH, Pomposova S, Fuentealba M, Alic N, Partridge L | title = The neuronal receptor tyrosine kinase Alk is a target for longevity | journal = Aging Cell | volume = 19 | issue = 5 | pages = e13137 | date = May 2020 | pmid = 32291952 | pmc = 7253064 | doi = 10.1111/acel.13137 | doi-access = free }}</ref> ALK is also a candidate [[thinness]] gene, as its genetic deletion leads to resistance to diet- and [[leptin]]-mutation-induced [[obesity]].<ref>{{cite journal | vauthors = Orthofer M, Valsesia A, Mägi R, Wang QP, Kaczanowska J, Kozieradzki I, Leopoldi A, Cikes D, Zopf LM, Tretiakov EO, Demetz E, Hilbe R, Boehm A, Ticevic M, Nõukas M, Jais A, Spirk K, Clark T, Amann S, Lepamets M, Neumayr C, Arnold C, Dou Z, Kuhn V, Novatchkova M, Cronin SJ, Tietge UJ, Müller S, Pospisilik JA, Nagy V, Hui CC, Lazovic J, Esterbauer H, Hagelkruys A, Tancevski I, Kiefer FW, Harkany T, Haubensak W, Neely GG, Metspalu A, Hager J, Gheldof N, Penninger JM | title = Identification of ALK in Thinness | journal = Cell | volume = 181 | issue = 6 | pages = 1246–1262.e22 | date = June 2020 | pmid = 32442405 | doi = 10.1016/j.cell.2020.04.034 | s2cid = 218762956 | doi-access = free }}</ref><ref group="N">In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.</ref>
 == Pathology ==
@@ Line 35: / Line 36: @@
 === Adenocarcinoma of the lung ===
-The [[EML4]]-ALK fusion gene is responsible for approximately 3-5% of [[non-small-cell lung cancer]] (NSCLC). The vast majority of cases are adenocarcinomas.<ref name=":14" /> Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.<ref>{{cite journal | vauthors = Patcas A, Chis AF, Militaru CF, Bordea IR, Rajnoveanu R, Coza OF, Hanna R, Tiberiu T, Todea DA | display-authors = 6 | title = An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance | journal = Bosnian Journal of Basic Medical Sciences | volume = 22 | issue = 1 | pages = 1–13 | date = February 2022 | pmid = 34082691 | pmc = 8860314 | doi = 10.17305/bjbms.2021.5859 }}</ref> The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry.<ref name=":14">{{Cite web|url=https://diagnostics.roche.com/us/en/products/tests/ventana-alk-_d5f3-cdx-assay0.html|title=VENTANA ALK (D5F3) CDx Assay|website=Diagnostics}}</ref>  Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.{{Citation needed|reason=Reliable source requested|date=October 2015}} ALK lung cancers are found in patients of all ages, although on average these patients tend to be younger.  ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.<ref name="pmid21252716">{{cite journal | vauthors = Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D | display-authors = 6 | title = International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma | journal = Journal of Thoracic Oncology | volume = 6 | issue = 2 | pages = 244–285 | date = February 2011 | pmid = 21252716 | pmc = 4513953 | doi = 10.1097/JTO.0b013e318206a221 }}</ref>
+The [[EML4]]-ALK fusion gene is responsible for approximately 3-5% of [[non-small-cell lung cancer]] (NSCLC). The vast majority of cases are adenocarcinomas.<ref name=":14" /> Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.<ref>{{cite journal | vauthors = Patcas A, Chis AF, Militaru CF, Bordea IR, Rajnoveanu R, Coza OF, Hanna R, Tiberiu T, Todea DA | title = An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance | journal = Bosnian Journal of Basic Medical Sciences | volume = 22 | issue = 1 | pages = 1–13 | date = February 2022 | pmid = 34082691 | pmc = 8860314 | doi = 10.17305/bjbms.2021.5859 }}</ref> The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana obtained approval in China and European Union countries to test this mutation by immunohistochemistry.<ref name=":14">{{Cite web|url=https://diagnostics.roche.com/us/en/products/tests/ventana-alk-_d5f3-cdx-assay0.html|title=VENTANA ALK (D5F3) CDx Assay|website=Diagnostics}}</ref>  Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.{{Citation needed|reason=Reliable source requested|date=October 2015}} ALK lung cancers are found in patients of all ages, although on average these patients tend to be younger.  ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors.<ref name="pmid21252716">{{cite journal | vauthors = Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D | title = International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma | journal = Journal of Thoracic Oncology | volume = 6 | issue = 2 | pages = 244–285 | date = February 2011 | pmid = 21252716 | pmc = 4513953 | doi = 10.1097/JTO.0b013e318206a221 }}</ref>
 === Gene rearrangements and overexpression in other tumours ===
-*Familial cases of [[neuroblastoma]]<ref name="pmid18724359">{{cite journal | vauthors = Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM | display-authors = 6 | title = Identification of ALK as a major familial neuroblastoma predisposition gene | journal = Nature | volume = 455 | issue = 7215 | pages = 930–935 | date = October 2008 | pmid = 18724359 | pmc = 2672043 | doi = 10.1038/nature07261 | bibcode = 2008Natur.455..930M }}</ref>
+*Familial cases of [[neuroblastoma]]<ref name="pmid18724359">{{cite journal | vauthors = Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM | title = Identification of ALK as a major familial neuroblastoma predisposition gene | journal = Nature | volume = 455 | issue = 7215 | pages = 930–935 | date = October 2008 | pmid = 18724359 | pmc = 2672043 | doi = 10.1038/nature07261 | bibcode = 2008Natur.455..930M }}</ref>
-*[[Inflammatory myofibroblastic tumor]]<ref name="pmid12112524">{{cite journal | vauthors = Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P | display-authors = 6 | title = Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor | journal = Genes, Chromosomes & Cancer | volume = 34 | issue = 4 | pages = 354–362 | date = August 2002 | pmid = 12112524 | doi = 10.1002/gcc.10033 | s2cid = 22808049 }}</ref><ref name="pmid10934142">{{cite journal | vauthors = Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA | display-authors = 6 | title = TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors | journal = The American Journal of Pathology | volume = 157 | issue = 2 | pages = 377–384 | date = August 2000 | pmid = 10934142 | pmc = 1850130 | doi = 10.1016/S0002-9440(10)64550-6 }}</ref>
+*[[Inflammatory myofibroblastic tumor]]<ref name="pmid12112524">{{cite journal | vauthors = Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P | title = Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor | journal = Genes, Chromosomes & Cancer | volume = 34 | issue = 4 | pages = 354–362 | date = August 2002 | pmid = 12112524 | doi = 10.1002/gcc.10033 | s2cid = 22808049 }}</ref><ref name="pmid10934142">{{cite journal | vauthors = Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA | title = TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors | journal = The American Journal of Pathology | volume = 157 | issue = 2 | pages = 377–384 | date = August 2000 | pmid = 10934142 | pmc = 1850130 | doi = 10.1016/S0002-9440(10)64550-6 }}</ref>
-* Adult<ref name="pmid22743654">{{cite journal | vauthors = Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC | title = ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients | journal = Modern Pathology | volume = 25 | issue = 11 | pages = 1516–1525 | date = November 2012 | pmid = 22743654 | doi = 10.1038/modpathol.2012.107 | doi-access = free }}</ref><ref name="pmid22252991">{{cite journal | vauthors = Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K | display-authors = 6 | title = Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method | journal = Cancer | volume = 118 | issue = 18 | pages = 4427–4436 | date = September 2012 | pmid = 22252991 | doi = 10.1002/cncr.27391 | s2cid = 9387860 | doi-access = free }}</ref> and pediatric<ref name="pmid21076462">{{cite journal | vauthors = Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA | title = Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum | journal = Modern Pathology | volume = 24 | issue = 3 | pages = 430–442 | date = March 2011 | pmid = 21076462 | doi = 10.1038/modpathol.2010.213 | doi-access = free }}</ref><ref name="pmid21213368">{{cite journal | vauthors = Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR | title = ALK rearrangement in sickle cell trait-associated renal medullary carcinoma | journal = Genes, Chromosomes & Cancer | volume = 50 | issue = 3 | pages = 146–153 | date = March 2011 | pmid = 21213368 | doi = 10.1002/gcc.20839 | s2cid = 39004672 }}</ref> [[renal cell carcinoma]]s
+* Adult<ref name="pmid22743654">{{cite journal | vauthors = Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC | title = ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients | journal = Modern Pathology | volume = 25 | issue = 11 | pages = 1516–1525 | date = November 2012 | pmid = 22743654 | doi = 10.1038/modpathol.2012.107 | doi-access = free }}</ref><ref name="pmid22252991">{{cite journal | vauthors = Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K | title = Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method | journal = Cancer | volume = 118 | issue = 18 | pages = 4427–4436 | date = September 2012 | pmid = 22252991 | doi = 10.1002/cncr.27391 | s2cid = 9387860 | doi-access = free }}</ref> and pediatric<ref name="pmid21076462">{{cite journal | vauthors = Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA | title = Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum | journal = Modern Pathology | volume = 24 | issue = 3 | pages = 430–442 | date = March 2011 | pmid = 21076462 | doi = 10.1038/modpathol.2010.213 | doi-access = free }}</ref><ref name="pmid21213368">{{cite journal | vauthors = Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR | title = ALK rearrangement in sickle cell trait-associated renal medullary carcinoma | journal = Genes, Chromosomes & Cancer | volume = 50 | issue = 3 | pages = 146–153 | date = March 2011 | pmid = 21213368 | doi = 10.1002/gcc.20839 | s2cid = 39004672 }}</ref> [[renal cell carcinoma]]s
-*[[Esophageal cancer|Esophageal squamous cell carcinoma]]<ref name="pmid17131471">{{cite journal | vauthors = Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH | display-authors = 6 | title = Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer | journal = World Journal of Gastroenterology | volume = 12 | issue = 44 | pages = 7104–7112 | date = November 2006 | pmid = 17131471 | pmc = 4087770 | doi = 10.3748/wjg.v12.i44.7104 | doi-access = free }}</ref><ref name="pmid18946602">{{cite journal | vauthors = Yaakup H, Sagap I, Fadilah SA | title = Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype | journal = Singapore Medical Journal | volume = 49 | issue = 10 | pages = e289–e292 | date = October 2008 | pmid = 18946602 }}</ref>
+*[[Esophageal cancer|Esophageal squamous cell carcinoma]]<ref name="pmid17131471">{{cite journal | vauthors = Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH | title = Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer | journal = World Journal of Gastroenterology | volume = 12 | issue = 44 | pages = 7104–7112 | date = November 2006 | pmid = 17131471 | pmc = 4087770 | doi = 10.3748/wjg.v12.i44.7104 | doi-access = free }}</ref><ref name="pmid18946602">{{cite journal | vauthors = Yaakup H, Sagap I, Fadilah SA | title = Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype | journal = Singapore Medical Journal | volume = 49 | issue = 10 | pages = e289–e292 | date = October 2008 | pmid = 18946602 }}</ref>
-* [[Breast cancer]],<ref name="exon">{{cite journal | vauthors = Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z | display-authors = 6 | title = Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers | journal = Molecular Cancer Research | volume = 7 | issue = 9 | pages = 1466–1476 | date = September 2009 | pmid = 19737969 | doi = 10.1158/1541-7786.MCR-08-0522 | doi-access = free }}</ref> notably the [[inflammatory breast cancer|inflammatory]] subtype<ref name="pmid22215853">{{cite journal | vauthors = Tuma RS | title = ALK gene amplified in most inflammatory breast cancers | journal = Journal of the National Cancer Institute | volume = 104 | issue = 2 | pages = 87–88 | date = January 2012 | pmid = 22215853 | doi = 10.1093/jnci/djr553 | doi-access = free }}</ref>
+* [[Breast cancer]],<ref name="exon">{{cite journal | vauthors = Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z | title = Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers | journal = Molecular Cancer Research | volume = 7 | issue = 9 | pages = 1466–1476 | date = September 2009 | pmid = 19737969 | doi = 10.1158/1541-7786.MCR-08-0522 | doi-access = free }}</ref> notably the [[inflammatory breast cancer|inflammatory]] subtype<ref name="pmid22215853">{{cite journal | vauthors = Tuma RS | title = ALK gene amplified in most inflammatory breast cancers | journal = Journal of the National Cancer Institute | volume = 104 | issue = 2 | pages = 87–88 | date = January 2012 | pmid = 22215853 | doi = 10.1093/jnci/djr553 | doi-access = free }}</ref>
 * [[Colorectal cancer|Colonic adenocarcinoma]]<ref name=exon />
-* [[Glioblastoma multiforme]]<ref name="pmid11809760">{{cite journal | vauthors = Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A | title = Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 14153–14158 | date = April 2002 | pmid = 11809760 | doi = 10.1074/jbc.M112354200 | doi-access = free }}</ref><ref name="pmid11278720">{{cite journal | vauthors = Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A | display-authors = 6 | title = Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin | journal = The Journal of Biological Chemistry | volume = 276 | issue = 20 | pages = 16772–16779 | date = May 2001 | pmid = 11278720 | doi = 10.1074/jbc.M010660200 | doi-access = free }}</ref>
+* [[Glioblastoma multiforme]]<ref name="pmid11809760">{{cite journal | vauthors = Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A | title = Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 14153–14158 | date = April 2002 | pmid = 11809760 | doi = 10.1074/jbc.M112354200 | doi-access = free }}</ref><ref name="pmid11278720">{{cite journal | vauthors = Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A | title = Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin | journal = The Journal of Biological Chemistry | volume = 276 | issue = 20 | pages = 16772–16779 | date = May 2001 | pmid = 11278720 | doi = 10.1074/jbc.M010660200 | doi-access = free }}</ref>
 * [[Anaplastic thyroid cancer]]<ref name="pmid21596819">{{cite journal | vauthors = Murugan AK, Xing M | title = Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene | journal = Cancer Research | volume = 71 | issue = 13 | pages = 4403–4411 | date = July 2011 | pmid = 21596819 | pmc = 3129369 | doi = 10.1158/0008-5472.CAN-10-4041 }}</ref>
@@ Line 50: / Line 51: @@
 {{main|ALK inhibitor}}
 * Xalkori ([[crizotinib]]), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.<ref>{{cite web|title=Xalkori Approved for Lung Cancer|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|publisher=FDA}}</ref> Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.
-In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.<ref>{{cite conference | vauthors = Gambacorti-Passerini CB, Dilda I, Giudici G, Perego A, Pavesi F, Guerra L, Borin L, Casaroli I, Fedele M, Verga L, Pogliani EM | display-authors = 6 | title = Clinical activity of crizotinib in advanced, chemoresistant ALK+ lymphoma patients. | conference = 2010 Annual Meeting of the American Society of Hematology | location = Orlando, Florida }}</ref><ref name="Gambacorti-Passerini_2011">{{cite journal | vauthors = Gambacorti-Passerini C, Messa C, Pogliani EM | title = Crizotinib in anaplastic large-cell lymphoma | journal = The New England Journal of Medicine | volume = 364 | issue = 8 | pages = 775–776 | date = February 2011 | pmid = 21345110 | doi = 10.1056/NEJMc1013224 | doi-access = free }}</ref><ref name="Gambacorti-Passerini_2014">{{cite journal | vauthors = Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, Messa C, Guerra L, Giudici G, Sala E, Mussolin L, Deeren D, King MH, Steurer M, Ordemann R, Cohen AM, Grube M, Bernard L, Chiriano G, Antolini L, Piazza R | display-authors = 6 | title = Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients | journal = Journal of the National Cancer Institute | volume = 106 | issue = 2 | pages = djt378 | date = February 2014 | pmid = 24491302 | doi = 10.1093/jnci/djt378 | doi-access = free }}</ref>
+In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.<ref>{{cite conference | vauthors = Gambacorti-Passerini CB, Dilda I, Giudici G, Perego A, Pavesi F, Guerra L, Borin L, Casaroli I, Fedele M, Verga L, Pogliani EM | title = Clinical activity of crizotinib in advanced, chemoresistant ALK+ lymphoma patients. | conference = 2010 Annual Meeting of the American Society of Hematology | location = Orlando, Florida }}</ref><ref name="Gambacorti-Passerini_2011">{{cite journal | vauthors = Gambacorti-Passerini C, Messa C, Pogliani EM | title = Crizotinib in anaplastic large-cell lymphoma | journal = The New England Journal of Medicine | volume = 364 | issue = 8 | pages = 775–776 | date = February 2011 | pmid = 21345110 | doi = 10.1056/NEJMc1013224 | doi-access = free }}</ref><ref name="Gambacorti-Passerini_2014">{{cite journal | vauthors = Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, Messa C, Guerra L, Giudici G, Sala E, Mussolin L, Deeren D, King MH, Steurer M, Ordemann R, Cohen AM, Grube M, Bernard L, Chiriano G, Antolini L, Piazza R | title = Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients | journal = Journal of the National Cancer Institute | volume = 106 | issue = 2 | pages = djt378 | date = February 2014 | pmid = 24491302 | doi = 10.1093/jnci/djt378 | doi-access = free }}</ref>
 * [[Ceritinib]] was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.<ref name="urlwww.accessdata.fda.gov">{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205755s000lbl.pdf | title = ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014 | publisher = United States Food and Drug Administration }}</ref>
 * [[Entrectinib]] (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three [[Trk receptor|Trk proteins]] (encoded by the three ''NTRK'' genes, respectively) as well as the ROS1, and ALK receptor [[Tyrosine kinase|tyrosine kinases.]] An open label, multicenter, global phase 2 clinical trial called [https://web.archive.org/web/20160812105405/https://www.startrktrials.com/ STARTRK-2] is currently underway to test the drug in patients with ROS1/[[Tropomyosin receptor kinase A|NTRK]]/ALK gene rearrangements.
@@ Line 66: / Line 67: @@
 == Further reading ==
 {{refbegin | 2}}
-* {{cite journal | vauthors = Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G | display-authors = 6 | title = ALK-positive lymphoma: a single disease with a broad spectrum of morphology | journal = Blood | volume = 91 | issue = 6 | pages = 2076–2084 | date = March 1998 | pmid = 9490693 | doi = 10.1182/blood.V91.6.2076 | doi-access = free }}
+* {{cite journal | vauthors = Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G | title = ALK-positive lymphoma: a single disease with a broad spectrum of morphology | journal = Blood | volume = 91 | issue = 6 | pages = 2076–2084 | date = March 1998 | pmid = 9490693 | doi = 10.1182/blood.V91.6.2076 | doi-access = free }}
-* {{cite journal | vauthors = Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW | display-authors = 6 | title = The emerging normal and disease-related roles of anaplastic lymphoma kinase | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 23 | pages = 2939–2953 | date = December 2004 | pmid = 15583856 | doi = 10.1007/s00018-004-4275-9 }}
+* {{cite journal | vauthors = Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW | title = The emerging normal and disease-related roles of anaplastic lymphoma kinase | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 23 | pages = 2939–2953 | date = December 2004 | pmid = 15583856 | doi = 10.1007/s00018-004-4275-9 }}
-* {{cite journal | vauthors = Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E | display-authors = 6 | title = TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations | journal = Blood | volume = 94 | issue = 9 | pages = 3265–3268 | date = November 1999 | pmid = 10556217 | doi = 10.1182/blood.V94.9.3265 }}
+* {{cite journal | vauthors = Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E | title = TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations | journal = Blood | volume = 94 | issue = 9 | pages = 3265–3268 | date = November 1999 | pmid = 10556217 | doi = 10.1182/blood.V94.9.3265 }}
-* {{cite journal | vauthors = Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C | display-authors = 6 | title = The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation | journal = FASEB Journal | volume = 15 | issue = 8 | pages = 1416–1418 | date = June 2001 | pmid = 11387242 | doi = 10.1096/fj.00-0678fje | s2cid = 44855189 }}
+* {{cite journal | vauthors = Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C | title = The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation | journal = FASEB Journal | volume = 15 | issue = 8 | pages = 1416–1418 | date = June 2001 | pmid = 11387242 | doi = 10.1096/fj.00-0678fje | doi-access = free | s2cid = 44855189 }}
-* {{cite journal | vauthors = Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G | display-authors = 6 | title = Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death | journal = Oncogene | volume = 21 | issue = 7 | pages = 1038–1047 | date = February 2002 | pmid = 11850821 | doi = 10.1038/sj.onc.1205152 | doi-access = free }}
+* {{cite journal | vauthors = Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G | title = Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death | journal = Oncogene | volume = 21 | issue = 7 | pages = 1038–1047 | date = February 2002 | pmid = 11850821 | doi = 10.1038/sj.onc.1205152 | doi-access = free }}
-* {{cite journal | vauthors = Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C | display-authors = 6 | title = ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes | journal = Blood | volume = 99 | issue = 6 | pages = 2100–2106 | date = March 2002 | pmid = 11877285 | doi = 10.1182/blood.V99.6.2100 | doi-access = free }}
+* {{cite journal | vauthors = Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C | title = ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes | journal = Blood | volume = 99 | issue = 6 | pages = 2100–2106 | date = March 2002 | pmid = 11877285 | doi = 10.1182/blood.V99.6.2100 | doi-access = free }}
 * {{cite journal | vauthors = Bonvini P, Gastaldi T, Falini B, Rosolen A | title = Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin | journal = Cancer Research | volume = 62 | issue = 5 | pages = 1559–1566 | date = March 2002 | pmid = 11888936 }}
-* {{cite journal | vauthors = Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, Ott G, Rosenwald A, Fernández A, Pulford K, Mason D, Morris SW, Santos E, Campo E | display-authors = 6 | title = Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity | journal = The American Journal of Pathology | volume = 160 | issue = 4 | pages = 1487–1494 | date = April 2002 | pmid = 11943732 | pmc = 1867210 | doi = 10.1016/S0002-9440(10)62574-6 }}
+* {{cite journal | vauthors = Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, Ott G, Rosenwald A, Fernández A, Pulford K, Mason D, Morris SW, Santos E, Campo E | title = Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity | journal = The American Journal of Pathology | volume = 160 | issue = 4 | pages = 1487–1494 | date = April 2002 | pmid = 11943732 | pmc = 1867210 | doi = 10.1016/S0002-9440(10)62574-6 }}
-* {{cite journal | vauthors = ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ | display-authors = 6 | title = Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma | journal = Blood | volume = 99 | issue = 12 | pages = 4540–4546 | date = June 2002 | pmid = 12036886 | doi = 10.1182/blood.V99.12.4540 | doi-access = free }}
+* {{cite journal | vauthors = ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ | title = Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma | journal = Blood | volume = 99 | issue = 12 | pages = 4540–4546 | date = June 2002 | pmid = 12036886 | doi = 10.1182/blood.V99.12.4540 | doi-access = free }}
 * {{cite journal | vauthors = Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG | title = Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines | journal = International Journal of Cancer | volume = 100 | issue = 1 | pages = 49–56 | date = July 2002 | pmid = 12115586 | doi = 10.1002/ijc.10435 | s2cid = 29955293 | doi-access = free }}
 {{refend}}

v t e Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1–50	CD1 a-c 1A 1B 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50
51–100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100
101–150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150
151–200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200
201–250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249
251–300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299
301–350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD327 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)