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==Functional regulation==
==Functional regulation==
In 1995, Kinesin-5 was determined to be post-translationally [[phosphorylated]] within its C-terminal tail.<ref name="pmid8548803">{{cite journal | author = Blangy A, Lane HA, d'Hérin P, Harper M, Kress M, Nigg EA | title = Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo | journal = Cell | volume = 83 | issue = 7 | pages = 1159–69 | year = 1995 | month = December | pmid = 8548803 | doi = }}</ref><ref name="pmid7753799">{{cite journal | authors = Sawin KE, MitchisonTJ | title = Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle | journal = Proc Natl Acad Sci U S A | volume = 92 | issue = 10 | pages = 4289-93 | pmid = 7753799 | pmc = 41929}}</ref> Once Kinesin-5 is phosphorylated at this residue in early prophase, it localizes to the mitotic spindle where it binds to microtubules. An additional phosphosite was identified on the Kinesin-5 tail in 2008, however, only approximately 3% of the total microtubule-associated Kinesin-5 is phosphorylated at this residues.<ref name="pmid19001501">{{cite journal | authors = Rapley J, Nicolas M, Groen A, Regue L, Bertran MT, Caelles C, Avruch J, Roig J | journal = J Cell Sci | volume = 121 | issue = Pt 23 | pages = 3912-21 | pmid = 19001501 | doi = 10.1242/jcs.035360}}</ref> While additional phosphosites or other post-translational modifications within the Kinesin-5 tail, stalk, and motor have been identified,<ref name="pmid18845538">{{cite journal | authors = Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M, Joshi HC, Zhou J | title = Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase | journal = J Biol Chem | volume = 283 | issue = 51 | pages = 35783-8 | pmid = 18845538 | doi = 10.1074/jbc.M806860200}}</ref><ref name="pmid19800237">{{cite journal | authors = Garcia K, Stumpff J, Duncan T, Su TT | title = Tyrosines in the kinesin-5 head domain are necessary for phosphorylation by Wee1 and for mitotic spindle integrity | journal = Curr Biol | volume = 19 | issue = 19 | pages = 1670-6 | pmid = 19800237 | pmc = 2762001 | doi = 10.1016/j.cub.2009.08.013}} no other modifications have been proven as necessary for Kinesin-5 to perform its necessary tasks in mitosis.
In 1995, Kinesin-5 was determined to be post-translationally [[phosphorylated]] within its C-terminal tail.<ref name="pmid8548803">{{cite journal | author = Blangy A, Lane HA, d'Hérin P, Harper M, Kress M, Nigg EA | title = Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo | journal = Cell | volume = 83 | issue = 7 | pages = 1159–69 | year = 1995 | month = December | pmid = 8548803 | doi = }}</ref><ref name="pmid7753799">{{cite journal | authors = Sawin KE, MitchisonTJ | title = Mutations in the kinesin-like protein Eg5 disrupting localization to the mitotic spindle | journal = Proc Natl Acad Sci U S A | volume = 92 | issue = 10 | pages = 4289-93 | pmid = 7753799 | pmc = 41929}}</ref> Once Kinesin-5 is phosphorylated at this residue in early prophase, it localizes to the mitotic spindle where it binds to microtubules. An additional phosphosite was identified on the Kinesin-5 tail in 2008, however, only approximately 3% of the total microtubule-associated Kinesin-5 is phosphorylated at this residues.<ref name="pmid19001501">{{cite journal | authors = Rapley J, Nicolas M, Groen A, Regue L, Bertran MT, Caelles C, Avruch J, Roig J | journal = J Cell Sci | volume = 121 | issue = Pt 23 | pages = 3912-21 | pmid = 19001501 | doi = 10.1242/jcs.035360}}</ref> While additional phosphosites or other post-translational modifications within the Kinesin-5 tail, stalk, and motor have been identified,<ref name="pmid18845538">{{cite journal | authors = Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M, Joshi HC, Zhou J | title = Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase | journal = J Biol Chem | volume = 283 | issue = 51 | pages = 35783-8 | pmid = 18845538 | doi = 10.1074/jbc.M806860200}}</ref><ref name="pmid19800237">{{cite journal | authors = Garcia K, Stumpff J, Duncan T, Su TT | title = Tyrosines in the kinesin-5 head domain are necessary for phosphorylation by Wee1 and for mitotic spindle integrity | journal = Curr Biol | volume = 19 | issue = 19 | pages = 1670-6 | pmid = 19800237 | pmc = 2762001 | doi = 10.1016/j.cub.2009.08.013}}</ref> no other modifications have been proven as necessary for Kinesin-5 to perform its necessary tasks in mitosis.
Kinesin-5 is also regulated through direct interaction with other proteins. The microtubule-associated protein, [[TPX2]], associates with Kinesin-5 in mitosis. Their interaction is necessary for Kinesin-5 localization to the mitotic spindle, for stabilizing the spindle, and for spindle pole segregation.[58][59][60] Kinesin-5 has been shown to interact with the [[dynactin]] subunit p150Glued [61] as well as many other cell cycle related proteins in vivo and in vitro,[18][62][63][64][65][66] however, additional experimentation is needed to confirm that their association is necessary for Kinesin-5 to function normally.
Kinesin-5 is also regulated through direct interaction with other proteins. The microtubule-associated protein, [[TPX2]], associates with Kinesin-5 in mitosis. Their interaction is necessary for Kinesin-5 localization to the mitotic spindle, for stabilizing the spindle, and for spindle pole segregation.[58][59][60] Kinesin-5 has been shown to interact with the [[dynactin]] subunit p150Glued [61] as well as many other cell cycle related proteins in vivo and in vitro,[18][62][63][64][65][66] however, additional experimentation is needed to confirm that their association is necessary for Kinesin-5 to function normally.

Revision as of 20:07, 20 June 2013

Template:PBB Kinesin family member 11 is a protein that in humans is encoded by the KIF11 gene.[1]

This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis.[1]

Function

KIF11 (also known as kinesin-5 and Eg5) is a homotetramer which cross-links anti-parallel microtubules in the mitotic spindle to maintain spindle bipolarity.[2][3][4][5] The motor domain or motor head is at the N-terminus and performs ATP hydrolysis and binds to microtubules. Kinesin-5 motors assemble into a bipolar homotetrameric structure that is capable of sliding apart bundles of anti-parallel oriented microtubules.[3][6][7] This motor is essential for mitosis in most organisms, wherein it participates in the self-assembly of the microtubule-based mitotic spindle, but is not otherwise required for cell viability. The motor may also play a role in the proper development of mammalian neuronal processes, including growth cone navigation and elongation.[8][9]

Function in mitosis

In most eukaryotic cells, Kinesin-5 is thought to form cross-bridges between pairs of oppositely oriented microtubules in prophase and prometaphase and drives apart duplicated centrosomes during the formation of the mitotic spindle.[3][7][10] This permits the establishment of a steady-state bipolar microtubule spindle structure.

Loss of Kinesin-5 function from the onset of mitosis in most eukaryotic organisms examined, including animals, plants, and fungi, results in catastrophic failure of mitosis.[11][12][13][14][15][16] This motor’s function is crucial during the onset of mitosis, wherein its loss of function results in the collapse, or inversion, of the spindle poles leaving centrally positioned centrosome pairs flanked by a radial array of microtubules with peripheral condensed chromosomes. The one exception to this effect is mitosis within the nematode, C. elegans, in which Kinesin-5 is not strictly essential for mitosis, but nonetheless has considerable impact on the overall fidelity of cell division.[17]

The discovery of small chemical inhibitors of human Kinesin-5 through a pioneering in vitro phenotypic screening on cancer cell lines has led to both the development of new anticancer therapeutic agents, and to novel tools to probe the mechanism of microtubule motor proteins.[16][18] This toolkit of allosteric inhibitors has been used to probe the specific role of Kinesin-5 in mitotic spindle assembly [19] as well as fine dissection of motor domain function.[20][21][22][23][24] Through this work it was found that, in mammalian cells, Kinesin-5 is required for the initial assembly of the mitotic spindle during prophase and prometaphase, but is dispensable to traverse subsequent anaphase during a round of mitosis.[2][19] Also, the binding of the Kinesin-5 inhibitors to an allosteric site on the motor interrupts the mechanism by which this enzyme converts the chemical energy of ATP hydrolysis into the mechanical work of moving microtubules, thus providing insight on how this enzyme works.

There are many models that attempt to explain the self-assembly of the mitotic spindle based upon microtubules as a structural element, and a set of microtubule motors, including Kinesin-5 to move and order them. Many of these models attempt to explain the steady state of the spindle at metaphase based on a predicted balance of motor forces acting in opposition within the spindle microtubules.[25][26] Still, it is not clear whether all the structural elements required for spindle assembly are known, or how the motors, including Kinesin-5, might be regulated in space and time. Such caveats make assessment of such models difficult. Recent data, however, finds that aspects of the ‘force balance’ model that posit spindle length and stability to be mediated by a balance between the minus-end directed microtubule sliding and plus-end directed microtubule sliding by opposing motors in insect cells, seems not to be the case in mammalian cells.[27] The process of self-assembly of the mitotic spindle remains a major unsolved question in cell biology, and a robust model awaits further details of the regulation and behavior of various microtubule motors and structural elements that compose this machinery.

Function in neurons

Although Kinesin-5 is required in all cells during cell division, it does not appear to play a major role in the metabolism of most non-dividing cells.[15][16] Among non-dividing cells, Kinesin-5 is most enriched within neurons, wherein it decorates the large microtubule bundles extending into axons and dendrites.[16][28] It has been shown, for example, that neurons remain fully viable in the background of a knock-down of Kinesin-5, but that changes in neuronal development and morphogenesis ensue. In developing neurons pharmacological inhibition and siRNA knockdown of KIF11 results in longer axons, more branches, fewer bouts of axon retraction and the inability of growth cones to turn on contact with repulsive substrates.[29][30][31] In migratory neurons, inhibition of KIF11 causes neurons to migrate in a random pattern and form shorter leading processes.[9] KIF11, like KIF15 and KIF23, is thought to act as a restrictor of short microtubules moving bi-directionally along the axon, exerting forces antagonistically to cytoplasmic dynein.[32][33] In mature neurons, KIF11 restricts the movement of short microtubules in dendrites, contributing to the formation of characteristic shape of dendrites.[34] KIF11 is also expressed in adult dorsal root ganglion neurons, although at a much diminished level. In adult neurons It has a similar effect on inhibiting the rate of short microtubule transport so pharmacological inhibition and siRNA knockdown of adult KIF11 may be a potential therapeutic tool for the augmentation of adult axon regeneration.[35] However, a clear in vivo role for Kinesin-5 in neurogenesis remains to be elucidated. Of note is that unusual peripheral neuropathies have not been observed in patients undergoing recent phase I or phase II trials of Kinesin-5 inhibitors for potential anti-cancer therapy.[36][37]

Functional regulation

In 1995, Kinesin-5 was determined to be post-translationally phosphorylated within its C-terminal tail.[2][38] Once Kinesin-5 is phosphorylated at this residue in early prophase, it localizes to the mitotic spindle where it binds to microtubules. An additional phosphosite was identified on the Kinesin-5 tail in 2008, however, only approximately 3% of the total microtubule-associated Kinesin-5 is phosphorylated at this residues.[39] While additional phosphosites or other post-translational modifications within the Kinesin-5 tail, stalk, and motor have been identified,[40][41] no other modifications have been proven as necessary for Kinesin-5 to perform its necessary tasks in mitosis.

Kinesin-5 is also regulated through direct interaction with other proteins. The microtubule-associated protein, TPX2, associates with Kinesin-5 in mitosis. Their interaction is necessary for Kinesin-5 localization to the mitotic spindle, for stabilizing the spindle, and for spindle pole segregation.[58][59][60] Kinesin-5 has been shown to interact with the dynactin subunit p150Glued [61] as well as many other cell cycle related proteins in vivo and in vitro,[18][62][63][64][65][66] however, additional experimentation is needed to confirm that their association is necessary for Kinesin-5 to function normally.


Pharmacological inhibitors

Inhibitors of KIF11 have been developed as chemotherapeutic agents in the treatment of cancer. Inhibition causes cells to undergo mitotic arrest, undergo apoptosis and form monoaster spindles.[42] The first KIF11 inhibitor, monastrol was discovered in a chemical screen of a large library of cell permeable compounds.[16][43] Various compounds, like monastrol have been tested in clinical trials but none have been fully developed and marketed as an anti-cancer treatment. Common KIF11 inhibitors include:

Human Mutations

Mutations and cancer

Mutations in the KIF11 gene convey resistance of mitotic cell lines to inhibitors such as monastrol and STLC.[47] For example, point mutations in the inhibitor binding pocket, R119A, D130A, L132A, I136A, L214A and E215A confer resistance to monastrol, while R119A, D130A and L214A mutations confer resistance to STLC. This may explain how tumor cells become drug-resistant to KIF11 inhibitors.

Mutations in MCLMR Syndrome

Germline mutations in KIF11 cause Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR).[48] This syndrome is observed as an autosomal dominant disorder with variable expressivity but can also be sporadic. It is characterized by mild-to-severe microcephaly, often associated with developmental delay, ocular defects and lymphedema, usually on the dorsum of the feet.[49]

References

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  47. ^ Tcherniuk S, van Lis R, Kozielski F, Skoufias DA (2010). "Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-L-cysteine in tumor derived cell lines". Biochem. Pharmacol. 79 (6): 864–72. doi:10.1016/j.bcp.2009.11.001. PMID 19896928. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  48. ^ Online Mendelian Inheritance in Man (OMIM): MCLMR - 152950
  49. ^ Schlögel MJ, Brouillard P, Mendola A, Fastré E, Cristofoli F, Devriendt K, Van Esch H, Vasudevan P, Soller M, Villanueva M, Singer A, Fieggen K, Carrera I, Loeys BL, van Laer L, Leroy JG, Claes K, De Baere E, Boon L, Vikkula M (2013). "All familial cases of MCLMR are caused by mutations in KIF11" (PDF) (13th Annual Meeting : Genetics of Human Development EXPOsed). Belgian Society of Human Genetics: P23. {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

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