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Kinesin-like protein KIF11

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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.Cite error: The <ref> tag has too many names (see the help page).[3][4][5] KIF11 is expressed in all cells during mitosis and in postmitotic neurons during development.[6] 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.[7][8][9] In migratory neurons, inhibition of KIF11 causes neurons to migrate in a random pattern and form shorter leading processes.[10] 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.[11][12] In mature neurons, KIF11 restricts the movement of short microtubules in dendrites, contributing to the formation of characteristic shape of dendrites.[13] 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.[14]

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.[15] The first KIF11 inhibitor, monastrol was discovered in a chemical screen of a large library of cell permeable compounds.[16][17] 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.[23] 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).[24] 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.[25]

References

  1. ^ a b "Entrez Gene: Kinesin family member 11".
  2. ^ Blangy A, Lane HA, d'Hérin P, Harper M, Kress M, Nigg EA (1995). "Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo". Cell. 83 (7): 1159–69. PMID 8548803. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b Kashina AS, Baskin RJ, Cole DG, Wedaman KP, Saxton WM, Scholey JM (1996). "A bipolar kinesin". Nature. 379 (6562): 270–2. doi:10.1038/379270a0. PMC 3203953. PMID 8538794. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ a b Sharp DJ, McDonald KL, Brown HM, Matthies HJ, Walczak C, Vale RD, Mitchison TJ, Scholey JM (1999). "The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles". J. Cell Biol. 144 (1): 125–38. PMC 2148119. PMID 9885249. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Sharp DJ, Yu KR, Sisson JC, Sullivan W, Scholey JM (1999). "Antagonistic microtubule-sliding motors position mitotic centrosomes in Drosophila early embryos". Nat. Cell Biol. 1 (1): 51–4. doi:10.1038/9025. PMID 10559864. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Ferhat L, Cook C, Chauviere M, Harper M, Kress M, Lyons GE, Baas PW (1998). "Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development". J. Neurosci. 18 (19): 7822–35. PMID 9742151. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Myers KA, Baas PW (2007). "Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array". J. Cell Biol. 178 (6): 1081–91. doi:10.1083/jcb.200702074. PMC 2064629. PMID 17846176. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Nadar VC, Ketschek A, Myers KA, Gallo G, Baas PW (2008). "Kinesin-5 is essential for growth-cone turning". Curr. Biol. 18 (24): 1972–7. doi:10.1016/j.cub.2008.11.021. PMC 2617768. PMID 19084405. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Nadar VC, Lin S, Baas PW (2012). "Microtubule redistribution in growth cones elicited by focal inactivation of kinesin-5". J. Neurosci. 32 (17): 5783–94. doi:10.1523/JNEUROSCI.0144-12.2012. PMC 3347042. PMID 22539840. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Falnikar A, Tole S, Baas PW (2011). "Kinesin-5, a mitotic microtubule-associated motor protein, modulates neuronal migration". Mol. Biol. Cell. 22 (9): 1561–74. doi:10.1091/mbc.E10-11-0905. PMC 3084678. PMID 21411631. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Liu M, Nadar VC, Kozielski F, Kozlowska M, Yu W, Baas PW (2010). "Kinesin-12, a mitotic microtubule-associated motor protein, impacts axonal growth, navigation, and branching". J. Neurosci. 30 (44): 14896–906. doi:10.1523/JNEUROSCI.3739-10.2010. PMC 3064264. PMID 21048148. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Lin S, Liu M, Mozgova OI, Yu W, Baas PW (2012). "Mitotic motors coregulate microtubule patterns in axons and dendrites". J. Neurosci. 32 (40): 14033–49. doi:10.1523/JNEUROSCI.3070-12.2012. PMID 23035110. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Yoon SY, Choi JE, Huh JW, Hwang O, Lee HS, Hong HN, Kim D (2005). "Monastrol, a selective inhibitor of the mitotic kinesin Eg5, induces a distinctive growth profile of dendrites and axons in primary cortical neuron cultures". Cell Motil. Cytoskeleton. 60 (4): 181–90. doi:10.1002/cm.20057. PMID 15751098. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Lin S, Liu M, Son YJ, Timothy Himes B, Snow DM, Yu W, Baas PW (2011). "Inhibition of Kinesin-5, a microtubule-based motor protein, as a strategy for enhancing regeneration of adult axons". Traffic. 12 (3): 269–86. doi:10.1111/j.1600-0854.2010.01152.x. PMC 3037443. PMID 21166743. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Zhang Y, Xu W (2008). "Progress on kinesin spindle protein inhibitors as anti-cancer agents". Anticancer Agents Med Chem. 8 (6): 698–704. PMID 18690830. {{cite journal}}: Unknown parameter |month= ignored (help)
  16. ^ a b Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999). "Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen". Science. 286 (5441): 971–4. PMID 10542155. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Gura, Trisha (21 September 2000). "A chemistry set for life". Nature International Weekly. Retrieved 31 December 2012.
  18. ^ Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ (2000). "Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5". J. Cell Biol. 150 (5): 975–88. PMC 2175262. PMID 10973989. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Compton DA (1999). "New tools for the antimitotic toolbox". Science. 286 (5441): 913–4. PMID 10577242. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ DeBonis S, Skoufias DA, Lebeau L, Lopez R, Robin G, Margolis RL, Wade RH, Kozielski F (2004). "In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities". Mol. Cancer Ther. 3 (9): 1079–90. PMID 15367702. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Hotha S, Yarrow JC, Yang JG, Garrett S, Renduchintala KV, Mayer TU, Kapoor TM (2003). "HR22C16: a potent small-molecule probe for the dynamics of cell division". Angew. Chem. Int. Ed. Engl. 42 (21): 2379–82. doi:10.1002/anie.200351173. PMID 12783501. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004). "Antitumor activity of a kinesin inhibitor". Cancer Res. 64 (9): 3276–80. PMID 15126370. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ 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)
  24. ^ Online Mendelian Inheritance in Man (OMIM): MCLMR - 152950
  25. ^ 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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