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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.[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.[18]

Function in neurons

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] KIF11 is expressed in all cells during mitosis and in postmitotic neurons during development.[8] 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.[17][18][19] 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.[20][21] In mature neurons, KIF11 restricts the movement of short microtubules in dendrites, contributing to the formation of characteristic shape of dendrites.[22] 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.[23]

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.[24] The first KIF11 inhibitor, monastrol was discovered in a chemical screen of a large library of cell permeable compounds.[16][25] 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.[31] 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).[32] 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.[33]

References

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  17. ^ 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)
  18. ^ 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)
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  32. ^ Online Mendelian Inheritance in Man (OMIM): MCLMR - 152950
  33. ^ 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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