View source for Kinesin family member 11

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{{Infobox_gene}} 
'''Kinesin-5''' is a molecular motor [[protein]] that is essential in [[mitosis]].<ref name="pmid23954229">{{cite journal |vauthors=Wojcik EJ, Buckley RS, Richard J, Liu L, Huckaba TM, Kim S | title = Kinesin-5: Cross-bridging mechanism to targeted clinical therapy | journal = Gene | volume = 531 | issue = 2 | pages = 133–49 |date=December 2013 | pmid = 23954229 | doi = 10.1016/j.gene.2013.08.004 | pmc=3801170}}</ref>  Kinesin-5 proteins are members of [[kinesin]] superfamily, which are nanomotors that move along microtubule tracks in the cell.  Named from studies in the early days of discovery, it is also known as '''kinesin family member 11''', encoded by the KIF11 [[gene]],<ref name="entrez">{{cite web | title = Entrez Gene: Kinesin family member 11 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=3832 }}</ref> or as '''BimC''', '''Eg5''' or '''N-2''', based on the founding members of this kinesin family.  The term kinesin-5 has been recommended based on a standardized nomenclature adopted by the scientific community.

Currently, there are over 70 different eukaryotic kinesin-5 proteins identified by sequence similarity.  Members of this protein family are known to be involved in various kinds of [[spindle apparatus|spindle]] dynamics and essential for mitosis. The function of this gene product includes chromosome positioning, [[centrosome]] separation and establishing a bipolar spindle during cell mitosis.<ref name="entrez"/>  The human Kinesin-5 protein has been actively studied for its role in mitosis and its potential as a therapeutic target for cancer treatment.

==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.<ref name="pmid8548803">{{cite journal |vauthors=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 |date=December 1995 | pmid = 8548803 | doi = 10.1016/0092-8674(95)90142-6}}</ref><ref name="pmid8538794">{{cite journal |vauthors=Kashina AS, Baskin RJ, Cole DG, Wedaman KP, Saxton WM, Scholey JM | title = A bipolar kinesin | journal = Nature | volume = 379 | issue = 6562 | pages = 270–2 |date=January 1996 | pmid = 8538794 | pmc = 3203953 | doi = 10.1038/379270a0 }}</ref><ref name="pmid9885249">{{cite journal |vauthors=Sharp DJ, McDonald KL, Brown HM, Matthies HJ, Walczak C, Vale RD, Mitchison TJ, Scholey JM | title = The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles | journal = J. Cell Biol. | volume = 144 | issue = 1 | pages = 125–38 |date=January 1999 | pmid = 9885249 | pmc = 2148119 | doi = 10.1083/jcb.144.1.125}}</ref><ref name="pmid10559864">{{cite journal |vauthors=Sharp DJ, Yu KR, Sisson JC, Sullivan W, Scholey JM | title = Antagonistic microtubule-sliding motors position mitotic centrosomes in Drosophila early embryos | journal = Nat. Cell Biol. | volume = 1 | issue = 1 | pages = 51–4 |date=May 1999 | pmid = 10559864 | doi = 10.1038/9025}}</ref> 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.<ref name="pmid8538794" /><ref name="pmid8083185">{{cite journal |vauthors=Cole DG, Saxton WM, Sheehan KB, Scholey JM | title = A "slow" homotetrameric kinesin-related motor protein purified from Drosophila embryos | journal = J Biol Chem | volume = 269 | issue = 37 | pages = 22913–6 | year = 1994 | pmid = 8083185 | pmc = 3201834}}</ref><ref name="pmid1406972">{{cite journal |vauthors=Sawin KE, LeGuellec K, Philippe M, Mitchison TJ | title = Mitotic spindle organization by a plus-end-directed microtubule motor | journal = Nature | volume = 359 | issue = 6395 | pages = 540–3 |date=October 1992 | pmid = 1406972 | doi = 10.1038/359540a0 }}</ref> 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.<ref name="pmid9742151">{{cite journal |vauthors=Ferhat L, Cook C, Chauviere M, Harper M, Kress M, Lyons GE, Baas PW | title = Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development | journal = J. Neurosci. | volume = 18 | issue = 19 | pages = 7822–35 |date=October 1998 | pmid = 9742151 | doi = }}</ref><ref name="pmid21411631">{{cite journal |vauthors=Falnikar A, Tole S, Baas PW | title = Kinesin-5, a mitotic microtubule-associated motor protein, modulates neuronal migration | journal = Mol Biol Cell | volume = 22 | issue = 9 | pages = 1561–74 | year = 2011 | pmid = 21411631 | pmc = 3084678 | doi = 10.1091/mbc.E10-11-0905}}</ref>

==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.<ref name="pmid8538794" /><ref name="pmid1406972"/><ref name="pmid23299893">{{cite journal |vauthors=Acar S, Carlson DB, Budamagunta MS, Yarov-Yarovoy V, Correia JJ, Ninonuevo MR, Jia W, Tao L, Leary JA, Voss JC, Evans JE, Scholey JM | title = The bipolar assembly domain of the mitotic motor kinesin-5 | journal = Nat Commun | issue = 4 | pages = 1343 | year = 2013 | pmid = 23299893 | pmc = 3562449 | doi = 10.1038/ncomms2348 | volume=4}}</ref>  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.<ref name="pmid8227131">{{cite journal | vauthors = Heck MM, Pereira A, Pesavento P, Yannoni Y, Spradling AC, Goldstein LS | title = The kinesin-like protein KLP61F is essential for mitosis in Drosophila | journal = J Cell Biol | volume = 123 | issue = 3 | pages = 665–79 | year = 1993 | pmid = 8227131 | pmc = 2200134 | doi=10.1083/jcb.123.3.665}}</ref><ref name="pmid17652157">{{cite journal | vauthors = Bannigan A, Scheible WR, Lukowitz W, Fagerstrom C, Wadsworth P, Somerville C, Baskin TI | title =  A conserved role for kinesin-5 in plant mitosis | journal = J Cell Sci | volume = 120 | issue = Pt 16 | pages = 2819–27| year = 2007 | pmid = 17652157 | doi = 10.1242/jcs.009506}}</ref><ref name="pmid2138511">{{cite journal | vauthors = Enos AP, Morris NR | last-author-amp = yes | title = Mutation of a gene that encodes a kinesin-like protein blocks nuclear division in A. nidulans | journal = Cell | volume = 60 | issue = 6 | pages = 1019–27 | year = 1990 | pmid = 2138511 | doi=10.1016/0092-8674(90)90350-N}}</ref><ref name="pmid2145514">{{cite journal | vauthors = Hagan I, Yanagida M | last-author-amp = yes | title = Novel potential mitotic motor protein encoded by the fission yeast cut7+ gene | journal = Nature | volume = 347 | issue = 6293 | pages = 563–6 | year = 1990| pmid = 2145514 | doi = 10.1038/347563a0}}</ref><ref name="pmid1629247">{{cite journal | vauthors = Sawin KE, Mitchison TJ, Wordeman LG | title = Evidence for kinesin-related proteins in the mitotic apparatus using peptide antibodies | journal = J Cell Sci | volume = 101 | issue = Pt 2 | pages = 303–13 | year = 1992 | pmid = 1629247}}</ref><ref name="pmid10542155">{{cite journal | vauthors = Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ | title = Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen | journal = Science | volume = 286 | issue = 5441 | pages = 971–4 | year = 1999 | pmid = 10542155 | doi=10.1126/science.286.5441.971}}</ref> 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, ''[[Caenorhabditis elegans|C. elegans]]'', in which Kinesin-5 is not strictly essential for mitosis, but nonetheless has considerable impact on the overall fidelity of cell division.<ref name="pmid15548597">{{cite journal | vauthors = Bishop JD, Han Z, Schumacher JM | title = The Caenorhabditis elegans Aurora B kinase AIR-2 phosphorylates and is required for the localization of a BimC kinesin to meiotic and mitotic spindles | journal = Mol Biol Cell | volume = 16 | issue = 2 | pages = 742–56| year = 2005 | pmid = 15548597 | pmc = 545908 | doi = 10.1091/mbc.E04-08-0682}}</ref>

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.<ref name="pmid10542155"/><ref name="pmid15367702">{{cite journal | vauthors = DeBonis S, Skoufias DA, Lebeau L, Lopez R, Robin G, Margolis RL, Wade RH, Kozielski F | title = In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities | journal = Mol Cancer Ther | volume = 3 | issue = 9 | pages = 1079–90 | year = 2004 | pmid = 15367702}}</ref>   This toolkit of allosteric inhibitors has been used to probe the specific role of Kinesin-5 in mitotic spindle assembly <ref name="pmid10973989">{{cite journal | vauthors = Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ | title = Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin | journal = J Cell Biol | volume = 150 | issue = 5 | pages = 975–88 | year = 2000 | pmid = 10973989 | pmc = 2175262 | doi=10.1083/jcb.150.5.975}}</ref> as well as fine dissection of motor domain function.<ref name="pmid15476401">{{cite journal | vauthors = Brier S, Lemaire D, Debonis S, Forest E, Kozielski F | title = Identification of the protein binding region of S-trityl-L-cysteine, a new potent inhibitor of the mitotic kinesin Eg5 | journal = Biochemistry | volume = 43 | issue = 41 | pages = 13072–82 | year = 2004 | pmid = 15476401 | doi = 10.1021/bi049264e}}</ref><ref name="pmid20513406">{{cite journal | vauthors = Larson AG, Naber N, Cooke R, Pate E, Rice SE | title = The conserved L5 loop establishes the pre-powerstroke conformation of the Kinesin-5 motor, eg5 | journal = Biophys J | volume = 98 | issue = 11 | pages = 2619–27 | year = 2010 | pmid = 20513406 | pmc = 2877332 | doi = 10.1016/j.bpj.2010.03.014}}</ref><ref name="pmid20299460">{{cite journal | vauthors = Kim ED, Buckley R, Learman S, Richard J, Parke C, Worthylake DK, Wojcik EJ, Walker RA, Kim S | title =  Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core | journal = J Biol Chem | volume = 285 | issue = 24 | pages = 18650–61| year = 2010 | pmid = 20299460 | pmc = 2881790 | doi = 10.1074/jbc.M109.092072}}</ref><ref name="pmid15287721">{{cite journal | vauthors = Wojcik EJ, Dalrymple NA, Alford SR, Walker RA, Kim S | title = Disparity in allosteric interactions of monastrol with Eg5 in the presence of ADP and ATP: a difference FT-IR investigation | journal = Biochemistry | volume = 43 | issue = 31 | pages = 9939–49 | year = 2004 | pmid = 15287721 | doi = 10.1021/bi048982y}}</ref><ref name="pmid21127071">{{cite journal | vauthors = Liu L, Parameswaran S, Liu J, Kim S, Wojcik EJ | title = Loop 5-directed compounds inhibit chimeric kinesin-5 motors: implications for conserved allosteric mechanisms | journal = J Biol Chem | volume = 286 | issue = 8 | pages = 6201–10| year = 2011 | pmid = 21127071 | pmc = 3057856 | doi = 10.1074/jbc.M110.154989}}</ref>  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.<ref name="pmid8548803"/><ref name="pmid10973989"/>  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.<ref name="pmid20930139">{{cite journal | vauthors = Mogilner A, Craig E | author-link = Alex Mogilner | title = Towards a quantitative understanding of mitotic spindle assembly and mechanics | journal = J Cell Sci | volume = 123 | issue = Pt 20 | pages = 3435–45 | year = 2010| pmid = 20930139 | pmc = 2951465 | doi = 10.1242/jcs.062208}}</ref><ref name="pmid11641489">{{cite journal | vauthors = Karsenti E, Vernos I | title = The mitotic spindle: a self-made machine | journal = Science | volume = 294 | issue = 5542 | pages = 543–7 | year =  2001| pmid = 11641489 | doi = 10.1126/science.1063488}}</ref> 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.<ref name="pmid22832270">{{cite journal | vauthors = Florian S, Mayer TU | title = The functional antagonism between Eg5 and dynein in spindle bipolarization is not compatible with a simple push-pull model | journal = Cell Rep | volume = 1 | issue = 5 | pages = 408–16 | year = 2012 | pmid = 22832270 | doi = 10.1016/j.celrep.2012.03.006}}</ref>  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.<ref name="pmid1629247"/><ref name="pmid10542155"/>  Among non-dividing cells, Kinesin-5 is most enriched within neurons, wherein it decorates the large microtubule bundles extending into axons and dendrites.<ref name="pmid10542155"/><ref name="pmid14983520">{{cite journal | vauthors = Haque SA, Hasaka TP, Brooks AD, Lobanov PV, Baas PW | title = Monastrol, a prototype anti-cancer drug that inhibits a mitotic kinesin, induces rapid bursts of axonal outgrowth from cultured postmitotic neurons | journal = Cell Motil Cytoskeleton | volume = 58 | issue = 1 | pages = 10–6 | year = 2004 | pmid = 14983520 | doi = 10.1002/cm.10176}}</ref>  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 cone]]s to turn on contact with repulsive substrates.<ref name="pmid17846176">{{cite journal |vauthors=Myers KA, Baas PW | title = Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array | journal = J. Cell Biol. | volume = 178 | issue = 6 | pages = 1081–91 |date=September 2007 | pmid = 17846176 | pmc = 2064629 | doi = 10.1083/jcb.200702074 }}</ref><ref name="pmid19084405">{{cite journal |vauthors=Nadar VC, Ketschek A, Myers KA, Gallo G, Baas PW | title = Kinesin-5 is essential for growth-cone turning | journal = Curr. Biol. | volume = 18 | issue = 24 | pages = 1972–7 |date=December 2008 | pmid = 19084405 | pmc = 2617768 | doi = 10.1016/j.cub.2008.11.021 }}</ref><ref name="pmid22539840">{{cite journal |vauthors=Nadar VC, Lin S, Baas PW | title = Microtubule redistribution in growth cones elicited by focal inactivation of kinesin-5 | journal = J. Neurosci. | volume = 32 | issue = 17 | pages = 5783–94 |date=April 2012 | pmid = 22539840 | pmc = 3347042 | doi = 10.1523/JNEUROSCI.0144-12.2012 }}</ref> In migratory neurons, inhibition of KIF11 causes neurons to migrate in a random pattern and form shorter leading processes.<ref name="pmid21411631"/> 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]].<ref name="pmid21048148">{{cite journal |vauthors=Liu M, Nadar VC, Kozielski F, Kozlowska M, Yu W, Baas PW | title = Kinesin-12, a mitotic microtubule-associated motor protein, impacts axonal growth, navigation, and branching | journal = J. Neurosci. | volume = 30 | issue = 44 | pages = 14896–906 |date=November 2010 | pmid = 21048148 | pmc = 3064264 | doi = 10.1523/JNEUROSCI.3739-10.2010 }}</ref><ref name="pmid23035110">{{cite journal |vauthors=Lin S, Liu M, Mozgova OI, Yu W, Baas PW | title = Mitotic motors coregulate microtubule patterns in axons and dendrites | journal = J. Neurosci. | volume = 32 | issue = 40 | pages = 14033–49 |date=October 2012 | pmid = 23035110 | doi = 10.1523/JNEUROSCI.3070-12.2012 | pmc=3482493}}</ref> In mature neurons, KIF11 restricts the movement of short microtubules in dendrites, contributing to the formation of characteristic shape of dendrites.<ref name="pmid15751098">{{cite journal |vauthors=Yoon SY, Choi JE, Huh JW, Hwang O, Lee HS, Hong HN, Kim D | title = Monastrol, a selective inhibitor of the mitotic kinesin Eg5, induces a distinctive growth profile of dendrites and axons in primary cortical neuron cultures | journal = Cell Motil. Cytoskeleton | volume = 60 | issue = 4 | pages = 181–90 |date=April 2005 | pmid = 15751098 | doi = 10.1002/cm.20057 }}</ref> 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.<ref name="pmid21166743">{{cite journal |vauthors=Lin S, Liu M, Son YJ, Timothy Himes B, Snow DM, Yu W, Baas PW | title = Inhibition of Kinesin-5, a microtubule-based motor protein, as a strategy for enhancing regeneration of adult axons | journal = Traffic | volume = 12 | issue = 3 | pages = 269–86 |date=March 2011 | pmid = 21166743 | pmc = 3037443 | doi = 10.1111/j.1600-0854.2010.01152.x }}</ref> 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.<ref name="pmid22825217">{{cite journal | vauthors = Rath O, Kozielski F | title = Kinesins and cancer | journal = Nat Rev Cancer | volume = 12 | issue = 8 | pages = 527–39 | pmid = 22825217 | doi = 10.1038/nrc3310 | date=Aug 2012}}</ref><ref name="pmid23434636">{{cite journal | author = El-Nassan HB | title = Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents | journal = Eur J Med Chem | volume = 62 | pages = 614–31 | year = 2012 | pmid = 23434636 | doi = 10.1016/j.ejmech.2013.01.031}}</ref>

==Functional regulation==
In 1995, Kinesin-5 was determined to be post-translationally [[phosphorylated]] within its C-terminal tail.<ref name="pmid8548803"/><ref name="pmid7753799">{{cite journal | vauthors = Sawin KE, Mitchison TJ | 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 | year = 1995 | pmid = 7753799 | pmc = 41929 | doi=10.1073/pnas.92.10.4289}}</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 | vauthors = 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 | year = 2008 | pmid = 19001501 | doi = 10.1242/jcs.035360 | title=The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. | pmc=4066659}}</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 | vauthors = 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 | year = 2008 | pmid = 18845538 | doi = 10.1074/jbc.M806860200}}</ref><ref name="pmid19800237">{{cite journal | vauthors = 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 | year = 2009 | 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.<ref name="pmid18372177">{{cite journal | vauthors = Eckerdt F, Eyers PA, Lewellyn AL, Prigent C, Maller JL | title = Spindle pole regulation by a discrete Eg5-interacting domain in TPX2 | journal = Curr Biol | volume = 18 | issue = 7 | pages = 519–25 | year = 2008 | pmid = 18372177 | pmc = 2408861 | doi = 10.1016/j.cub.2008.02.077}}</ref><ref name="pmid21969468">{{cite journal | vauthors = Ma N, Titus J, Gable A, Ross JL, Wadsworth P | title = TPX2 regulates the localization and activity of Eg5 in the mammalian mitotic spindle | journal = J Cell Biol |  volume = 195 | issue = 1 | pages = 87–98 | year = 2011 | pmid = 21969468 | pmc = 3187703 | doi = 10.1083/jcb.201106149 }}</ref>  Kinesin-5 has been shown to interact with the [[dynactin]] subunit p150Glued<ref name="pmid9235942">{{cite journal | vauthors = Blangy A, Arnaud L, Nigg EA | title = Phosphorylation by p34cdc2 protein kinase regulates binding of the kinesin-related motor HsEg5 to the dynactin subunit p150 | journal = J Biol Chem | volume = 272 | issue = 31 | pages = 19418–24 | year = 1997 | pmid = 9235942 | doi=10.1074/jbc.272.31.19418}}</ref> as well as many other cell cycle related proteins in vivo and in vitro,<ref name="pmid23368718">{{cite journal | vauthors = Iwakiri Y, Kamakura S, Hayase J, Sumimoto H | title = Interaction of NuMA protein with the kinesin Eg5: its possible role in bipolar spindle assembly and chromosome alignment | journal = Biochem J | volume = 451| issue = 2 | pages = 195–204 | year = 2013 | pmid = 23368718 | doi = 10.1042/BJ20121447}}</ref><ref name="pmid11231570">{{cite journal | vauthors = Wilde A, Lizarraga SB, Zhang L, Wiese C, Gliksman NR, Walczak CE, Zheng Y | title = Ran stimulates spindle assembly by altering microtubule dynamics and the balance of motor activities | journal = Nat Cell Biol | volume = 3 | issue = 3 | pages = 221–7 | year = 2001 | pmid = 11231570 | doi = 10.1038/35060000}}</ref><ref name="pmid16631581">{{cite journal | vauthors = Koffa MD, Casanova CM, Santarella R, Kocher T, Wilm M, Mattaj IW | title = HURP is part of a Ran-dependent complex involved in spindle formation | journal = Curr Biol | volume = 16 | issue = 8 | pages = 743–54 | year = 2006 | pmid = 16631581 | doi = 10.1016/j.cub.2006.03.056}}</ref> however, additional experimentation is needed to confirm that their association is necessary for Kinesin-5 to function normally.

==Molecular mechanism==
'''ATP hydrolysis'''

Kinesin-5, like all motor proteins, breaks down ATP into ADP and inorganic phosphate, using a water molecule, and converts the chemical energy to force and motion along microtubules.  Kinetic experiments reveal rates of how fast intermediate steps in catalysis occur and the most extensive set of studies on Kinesin-5 kinetics has been on the human protein.<ref name="pmid12323373">{{cite journal | vauthors = Maliga Z, Kapoor TM, Mitchison TJ | title = Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5 | journal = Chem Biol | volume = 9 | issue = 9 | pages = 989–96 | year = 2002 | pmid = 12323373 | doi=10.1016/S1074-5521(02)00212-0}}</ref><ref name="pmid17014086">{{cite journal | vauthors = Cochran JC, Krzysiak TC, Gilbert SP | title = Pathway of ATP hydrolysis by monomeric kinesin Eg5 | journal = Biochemistry | volume = 45 | issue = 40 | pages = 12334–44 | year = 2006 | pmid = 17014086 | pmc = 2288585 | doi = 10.1021/bi0608562}}</ref>  X-ray crystallography, cryo-electron microscopy, and real-time infrared spectroscopy have been used to measure the structure of Kinesin-5 in the different catalytic intermediate states.  Changes in the secondary structure, or conformational switching, is required to convert and amplify biochemical changes in the catalytic active site into larger movements necessary for cellular motion.<ref name="pmid8896589">{{cite journal | author = Vale RD | title = Switches, latches, and amplifiers: common themes of G proteins and molecular motors | journal = J Cell Biol | volume = 135 | issue = 2 | pages = 291–302 | year = 1996 | pmid = 8896589 | pmc = 2121043 | doi=10.1083/jcb.135.2.291}}</ref><ref name="pmid11801720">{{cite journal | vauthors = Kull FJ, Endow SA | title = Kinesin: switch I & II and the motor mechanism | journal = J Cell Sci | volume = 115 | issue = Pt 1 | pages = 15–23 | year = 2002 | pmid = 11801720}}</ref>  For example, the first step of ATP hydrolysis, which is the attack of the terminal phosphate of ATP by a water molecule, had not been observed by x-ray crystallography in any kinesin protein, until recently in Kinesin-5.<ref name="pmid20018897">{{cite journal | vauthors = Parke CL, Wojcik EJ, Kim S, Worthylake DK | title = ATP hydrolysis in Eg5 kinesin involves a catalytic two-water mechanism | journal = J Biol Chem | volume = 285 | issue = 8 | pages = 5859–67 | year = 2010 | pmid = 20018897 | pmc = 2820811 | doi = 10.1074/jbc.M109.071233}}</ref>  This crystal structure showed that there was not one, but rather two, water molecules and they are in close association with each other.  A two-water catalytic model was proposed and confirmed by an alternate method to track Kinesin-5 catalysis in real-time<ref name="pmid20154092">{{cite journal | vauthors = Jun B, Kim S | title = Real-time structural transitions are coupled to chemical steps in ATP hydrolysis by Eg5 kinesin | journal = J Biol Chem | volume = 285 | issue = 15 | pages = 11073–7 | year = 2010 | pmid = 20154092 | pmc = 2856982 | doi = 10.1074/jbc.C110.103762}}</ref> and in a kinesin protein in a different subfamily.<ref name="pmid23500491">{{cite journal | vauthors = Chan Q, Nitta R, Inoue S, Hirokawa N | title = Structural Basis for the ATP-Induced Isomerization of Kinesin | journal = J Mol Biol | volume = 425 | issue = 11 | pages = 1869–80 | year = 2013 | pmid = 23500491 | doi = 10.1016/j.jmb.2013.03.004}}</ref>  Two-water catalytic models also are proposed in a divergent motor protein, myosin, and observed experimentally in one of its crystal structures.<ref name="pmid15049682">{{cite journal | vauthors = Onishi H, Mochizuki N, Morales MF | title = On the myosin catalysis of ATP hydrolysis | volume = 43 | issue = 13 | pages = 3757–63 | year = 2004 | pmid = 15049682 | doi = 10.1021/bi040002m | journal=Biochemistry}}</ref><ref name="pmid8611530">{{cite journal | vauthors = Smith CA, Rayment I | title = X-ray structure of the magnesium(II).ADP.vanadate complex of the Dictyostelium discoideum myosin motor domain to 1.9 A resolution | journal = Biochemistry | volume = 35 | issue = 17 | pages = 5404–17 | year = 1996 | pmid = 8611530 | doi = 10.1021/bi952633+}}</ref>

'''Mechanical Properties'''

The antiparallel tetrameric organization of the Kinesin-5 family is fundamentally different from the majority of other kinesins that are dimers, such as the well-characterized conventional Kinesin-1 ([[KIF5B]]).  Conventional kinesin dimerizes in such a manner that the catalytic (head) domains are together on one end of the complex to facilitate hand-over-hand movement along a microtubule that enables long-range, directed transport of cellular cargoes.  The unique assembly of Kinesin-5 proteins not only organizes the protein complex for a different cellular function (antiparallel microtubule sliding, described above) but also made it difficult to study the mechanical properties of the motor using the classical experiments that were designed for dimeric kinesins.  These obstacles have been overcome by either adapting the original experiments to analyze the tetrameric organization of Kinesin-5, or by working with shorter Kinesin-5 proteins that form dimers like conventional kinesin.

The most striking outcomes of the analysis of Kinesin-5 motility is that it is slow – about 10 times slower than conventional Kinesin-1 – with a velocity in the range of 50 nanometers per second and that it could generate very high levels of mechanical force (7-9 picoNewtons per molecule).  These values come from three types of experimental data: microtubule gliding assays, single molecule motility assays, and [[optical trap]] assays. In microtubule gliding assays, kinesins are attached to a glass surface and microtubules are laid down over the top.  Since the motors are attached to the glass, their motile behavior translates into movement of the microtubule across the anchored kinesins, akin to someone [[crowd surfing]].  These experiments gave us the first analysis of Kinesin-5 motility.[[File:Kif11 wiki movie.gif|thumb|Microtubule gliding by Kinesin-5]]  By attaching microtubules to the glass surface first, then adding Kinesin-5 with free microtubules in solution, it was possible to adapt the microtubule gliding assays to show that Kinesin-5 can crosslink two microtubules and move them in opposite directions.  This experiment showed that Kinesin-5 was indeed capable of carrying out the role that had been proposed for it in mitosis – sliding oppositely oriented microtubules in the mitotic spindle.  To study the behavior of individual Kinesin-5 molecules, single molecule motility assays were performed by attaching microtubules to a glass surface, then adding a dilute solution of Kinesin-5 with a [[fluorophore]] attached.  This experimental setup enables the observer to follow separate Kinesin-5 molecules as they “walk” along the microtubule, providing not only information about velocity, but also about [[processivity]] – the ability of a kinesin to take multiple steps along the microtubule without dissociating.  In single molecule motility assays, velocities for Kinesin-5 were similar to those seen in microtubule gliding assays, and the motor was observed to be weakly processive.<ref name="pmid18678707">{{cite journal | vauthors = Kapitein LC, Kwok BH, Weinger JS, Schmidt CF, Kapoor TM, Peterman EJ | title = Microtubule cross-linking triggers the directional motility of kinesin-5 | journal = J Cell Biol | volume = 182 | issue = 3 | pages = 421–8 | year = 2008 | pmid = 18678707 | pmc = 2500128 | doi = 10.1083/jcb.200801145}}</ref><ref name="pmid15458652">{{cite journal | vauthors = Kwok BH, Yang JG, Kapoor TM | title = The rate of bipolar spindle assembly depends on the microtubule-gliding velocity of the mitotic kinesin Eg5 | journal = Curr Biol | volume = 14 | issue = 4 | pages = 1783–8 | year = 2004 | pmid = 15458652 | doi = 10.1016/j.cub.2004.09.052}}</ref><ref name="pmid21236672">{{cite journal | vauthors = Weinger JS, Qiu M, Yang G, Kapoor TM | title = A nonmotor microtubule binding site in kinesin-5 is required for filament crosslinking and sliding | journal = Curr Biol | volume = 21 | issue = 2 | year = 2011 | pmid = 21236672 | pmc = 3049310 | doi = 10.1016/j.cub.2010.12.038 | pages=154–160}}</ref> In optical trap experiments, Kinesin-5 molecules are attached to a bead that can be held in place by a finely focused laser.  By moving the bead close to a microtubule, the kinesin can bind to the microtubule and begin stepping, pulling the bead along behind it.  Since the bead is being held in place by the trap laser, it acts like a spring and exerts a force that resists the forward movement of the kinesin.  This allows for the measurement of the stall force – the maximum amount of force that can be exerted by a motor before it releases from the microtubule.  Optical trap experiments showed that Kinesin-5 generates a maximum of 7 picoNewtons of force before releasing, but that its behavior differs from that of other kinesins in that there was no observable plateau phase in which the motor “struggles” at its maximal force generation before letting go.<ref name="pmid19751672">{{cite journal | vauthors = Valentine MT, Block SM | title = Force and premature binding of ADP can regulate the processivity of individual Eg5 dimers | journal = Biophys J | volume = 97 | issue = 6 | pages = 1671–7 | year = 2009 | pmid = 19751672 | pmc = 2749793 | doi = 10.1016/j.bpj.2009.07.013}}</ref><ref name="pmid16604065">{{cite journal | vauthors = Valentine MT, Fordyce PM, Krzysiak TC, Gilbert SP, Block SM | title = Individual dimers of the mitotic kinesin motor Eg5 step processively and support substantial loads in vitro | journal = Nat Cell Biol| volume = 8 | issue = 5 | pages = 470–6 | year = 2006 | pmid = 16604065 | pmc = 1523314 | doi = 10.1038/ncb1394}}</ref>  Extrapolation of kinetic data suggests that the maximal observed force generated in the optical trap by Kinesin-5 is actually an underestimate and that it theoretically can exert up to 9 picoNewtons of force as a maximum, although further experimental work is required to test this.

==Pharmacological inhibitors==
Inhibitors of KIF11 have been developed as chemotherapeutic agents in the treatment of cancer. Drugs that specifically inhibit only human Kinesin-5 are alternatives to the taxanes and vinc alkaloids that target microtubules, and thus all cells, and that are currently used clinically.  Inhibition of Kinesin-5 causes cells to undergo mitotic arrest, undergo apoptosis and form monoaster spindles.<ref name="pmid18690830">{{cite journal |vauthors=Zhang Y, Xu W | title = Progress on kinesin spindle protein inhibitors as anti-cancer agents | journal = Anticancer Agents Med Chem | volume = 8 | issue = 6 | pages = 698–704 |date=August 2008 | pmid = 18690830 | doi = 10.2174/1871520610808060698}}</ref> The first KIF11 inhibitor, [[monastrol]] was discovered in a chemical screen of a large library of cell permeable compounds.<ref name="pmid10542155"/><ref>{{cite journal|last=Gura|first=Trisha|title=A chemistry set for life|url=http://www.nature.com/nature/journal/v407/n6802/full/407282a0.html|accessdate=31 December 2012|newspaper=Nature International Weekly|date=21 September 2000|volume=407|doi=10.1038/35030189|pages=282–284}}</ref> Since then, over 100 different chemical classes of allosteric inhibitors have been identified in the scientific literature and they have a wide range in potency against human Kinesin-5.<ref name="pmid23434636"/><ref name="pmid19156502">{{cite journal | vauthors = Huszar D, Theoclitou ME, Skolnik J, Herbst R | title = Kinesin motor proteins as targets for cancer therapy | journal = Cancer Metastasis Rev | volume = 28 | issue = 1–2 | pages = 197–208 | year = 2009 | pmid = 19156502 | doi = 10.1007/s10555-009-9185-8}}</ref> Common KIF11 inhibitors include:
* [[monastrol]],<ref name="pmid10542155"/><ref name="pmid10973989"/><ref name="pmid10577242">{{cite journal | author = Compton DA | title = New tools for the antimitotic toolbox | journal = Science | volume = 286 | issue = 5441 | pages = 913–4 |date=October 1999 | pmid = 10577242 | doi = 10.1126/science.286.5441.913}}</ref>
* S-Trityl-L-cysteine (STLC),<ref name="pmid15367702"/>
* HR22C16,<ref name="pmid12783501">{{cite journal |vauthors=Hotha S, Yarrow JC, Yang JG, Garrett S, Renduchintala KV, Mayer TU, Kapoor TM | title = HR22C16: a potent small-molecule probe for the dynamics of cell division | journal = Angew. Chem. Int. Ed. Engl. | volume = 42 | issue = 21 | pages = 2379–82 |date=May 2003 | pmid = 12783501 | doi = 10.1002/anie.200351173 | url = }}</ref> and 
* CK0106023.<ref name="pmid15126370">{{cite journal |vauthors=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 | title = Antitumor activity of a kinesin inhibitor | journal = Cancer Res. | volume = 64 | issue = 9 | pages = 3276–80 |date=May 2004 | pmid = 15126370 | doi =  10.1158/0008-5472.can-03-3839}}</ref>

The majority of human Kinesin-5 inhibitors are selective, because they bind to a drug ‘hot spot’, composed of residues from the α2 and α3 helices and a flexible L5 loop on the surface of the motor domain.  This L5 loop has high sequence variability amongst the Kinesin-5 orthologs and other kinesins within the superfamily.  The L5 loop in human Kinesin-5 closes around the inhibitor and is open in the absence of inhibitor.<ref name="pmid11328809">{{cite journal |vauthors=Turner J, Anderson R, Guo J, Beraud C, Fletterick R, Sakowicz R | title = Crystal structure of the mitotic spindle kinesin Eg5 reveals a novel conformation of the neck-linker | journal = J. Biol. Chem. | volume = 276 | issue = 27 | pages = 25496–502 |date=July 2001 | pmid = 11328809 | doi = 10.1074/jbc.M100395200 }}</ref><ref name="pmid14672662">{{cite journal | vauthors = Yan Y, Sardana V, Xu B, Homnick C, Halczenko W, Buser CA, Schaber M, Hartman GD, Huber HE, Kuo LC | title = Inhibition of a mitotic motor protein: where, how, and conformational consequences | journal = J Mol Biol | volume = 335 | issue = 2 | pages = 547–54 | year = 2004 | pmid = 14672662 | doi=10.1016/j.jmb.2003.10.074}}</ref>  These structural changes are correlated with other changes in the catalytic active site. Other sites of inhibitor binding have been identified in the human Kinesin-5 motor domain.<ref name="pmid19236100">{{cite journal | vauthors = Learman SS, Kim CD, Stevens NS, Kim S, Wojcik EJ | title = NSC 622124 inhibits human Eg5 and other kinesins via interaction with the conserved microtubule-binding site | journal = Biochemistry | volume = 48 | issue = 8 | pages = 1754–62 | year = 2009 | pmid = 19236100 | pmc = 3244877 | doi = 10.1021/bi801291q}}</ref><ref name="pmid23305346">{{cite journal | vauthors = Ulaganathan V, Talapatra SK, Rath O, Pannifer A, Hackney DD, Kozielski F | title = Structural insights into a unique inhibitor binding pocket in kinesin spindle protein | journal = J Am Chem Soc | volume = 135 | issue = 6 | pages = 2263–72 | year = 2013 | pmid = 23305346 | doi = 10.1021/ja310377d}}</ref> For inhibitors that bind to the L5 pocket, the mechanism of inhibition is that they slow ADP release from the catalytic active site<ref name="pmid16342954">{{cite journal | vauthors = Cochran JC, Krzysiak TC, Gilbert SP | title = ATPase mechanism of Eg5 in the absence of microtubules: insight into microtubule activation and allosteric inhibition by monastrol | journal = Biochemistry | volume = 44 | issue = 50 | pages = 16633–48 | year = 2005 | pmid = 16342954 | pmc = 2270472 | doi = 10.1021/bi051724w}}</ref> and inhibit ATP-dependent directional motion.<ref name="pmid16892050">{{cite journal | vauthors = Kwok BH, Kapitein LC, Kim JH, Peterman EJ, Schmidt CF, Kapoor TM | title = Allosteric inhibition of kinesin-5 modulates its processive directional motility | journal = Nat Chem Biol | volume = 2 | issue = 9 | pages = 480–5 | year = 2006 | pmid = 16892050 | doi =10.1038/nchembio812}}</ref>  However, a previously unknown diffusive motion by Kinesin-5 along microtubules was uncovered when monastrol inhibited the motor domain.<ref name="pmid15182685">{{cite journal | vauthors = Crevel IM, Alonso MC, Cross RA | title = Monastrol stabilises an attached low-friction mode of Eg5 | journal = Curr Biol | volume = 14 | issue = 11 | pages = R411-2 | year = 2004 | pmid = 15182685 | doi = 10.1016/j.cub.2004.05.030}}</ref>

Small-molecule inhibitors are not only important tools for understanding nanomotors in cells;  they are also have potential for serving as tools in the clinic.  Induced by human Kinesin-5 inhibitors, mitotic arrest results in apoptosis in some tumor cell lines<ref name="pmid16627469">{{cite journal | authors = Liu M, Aneja R, Liu C, Sun L, Gao J, Wang H, Dong JT, Sarli V, Giannis A, Joshi HC, Zhou J | title = Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells | journal = J Biol Chem | volume = 281 | issue = 26 | pages = 18090–7 | year = 2006 | pmid = 16627469 | doi = 10.1074/jbc.M601324200}}</ref><ref name="pmid18974392">{{cite journal | authors = Orth JD, Tang Y, Shi J, Loy CT, Amendt C, Wilm C, Zenke FT, Mitchison TJ | title = Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate | journal = Mol Cancer Ther | volume = 7 | issue = 11 | pages = 3480–9 | year = 2008 | pmid = 18974392 | pmc = 2597169 | doi = 10.1158/1535-7163.MCT-08-0684}}</ref> and [[Patient derived tumor xenografts|human tumor xenograft]] models.<ref name="Mller 2005">{{cite journal | authors = Miller K, Ng C, Ang P, Brufsky AM, Lee SC, Dees EC, Piccart M, Verrill M, Wardley A, Loftiss J, Bal J, Yeoh S, Hodge J, Williams D, Dar M and Ho PTC | title = Phase II, open label study of SB-715992 (ispinesib) in subjects with advanced or metastatic breast cancer | journal =   | volume = 94 | issue = 28th Annual San Antonio Breast Cancer Symposium | pages = S70 | publisher =  | doi =  | pmid = | pmc = | url =  }}</ref>  With these promising preclinical studies, [[ispinesib]] (SB-715992; Cytokinetics/GSK), [[SB-743921]] from Cytokinetics/GSK,<ref name="pmid20031160">{{cite journal | authors = Deming D, Geiger P, Chen H, Kunnimalaiyaan M, Holen K | title = ZM336372 Induces Apoptosis Associated With Phosphorylation of GSK-3β in Pancreatic Adenocarcinoma Cell Lines | journal = Cancer Chemother Pharmacol | volume = 161 | issue = 1 | pages = 28–32 | year = 2010 | pmid = 20031160 | pmc = 3379885 | doi = 10.1016/j.jss.2009.06.013}}</ref> [[MK-0731]] from Merck,<ref name="pmid15808464">{{cite journal | authors = Cox CD, Breslin MJ, Mariano BJ, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Huber HE, Kohl NE, Torrent M, Yan Y, Kuo LC, Hartman GD | title = Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP | journal = Bioorg Med Chem Lett | volume = 15 | issue = 8 | pages = 2041–5 | year = 2005 | doi = 10.1016/j.bmcl.2005.02.055}}</ref> [[filanesib]] (ARRY-520) (Array BioPharma), and [[litronesib]] (LY2523355) (Eli Lilly) have entered into clinical trials.<ref name="pmid17186004">{{cite journal | authors = Kathman SJ, Williams DH, Hodge JP, Dar M | title = A Bayesian population PK-PD model of ispinesib-induced myelosuppression | journal = Clin Pharmacol Ther | volume = 81 | issue = 1 | pages = 88–94 | year = 2007 | pmid = 17186004 | doi = 10.1038/sj.clpt.6100021}}</ref><ref name="pmid20068098">{{cite journal | authors = Purcell JW, Davis J, Reddy M, Martin S, Samayoa K, Vo H, Thomsen K, Bean P, Kuo WL, Ziyad S, Billig J, Feiler HS, Gray JW, Wood KW, Cases S | title = Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer | journal = Clin Cancer Res | volume = 16 | issue = 2 | pages = 566–76 | year = 2010 | pmid = 20068098 | pmc = 2844774 | doi = 10.1158/1078-0432.CCR-09-1498}}</ref><ref name="pmid22139909">{{cite journal | authors = Khoury HJ, Garcia-Manero G, Borthakur G, Kadia T, Foudray MC, Arellano M, Langston A, Bethelmie-Bryan B, Rush S, Litwiler K, Karan S, Simmons H, Marcus AI, Ptaszynski M, Kantarjian H | title = A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias | journal = Cancer | volume = 118 | issue = 14 | year = 2012 | pmid = 22139909 | doi = 10.1002/cncr.26664 | pages=3556–64 | pmc=4984525}}</ref>  Although second-generation Kinesin-5 inhibitors have had better success, none have been fully developed and marketed as an anti-cancer treatment.
 
The role of specific residues in the L5 pocket (L5, α2, and α3) in human Kinesin-5 has been tested,<ref name="pmid15476401"/><ref name="pmid20299460"/><ref name="pmid21872609">{{cite journal | vauthors = Harrington TD, Naber N, Larson AG, Cooke R, Rice SE, Pate E | title = Analysis of the interaction of the Eg5 Loop5 with the nucleotide site | journal = J Theor Biol | volume = 289 | pages = 107–15 | year = 2011 | pmid = 21872609 | pmc = 3191284 | doi = 10.1016/j.jtbi.2011.08.017}}</ref><ref name="pmid21148480">{{cite journal | vauthors = Behnke-Parks WM, Vendome J, Honig B, Maliga Z, Moores C, Rosenfeld SS | title = Loop L5 acts as a conformational latch in the mitotic kinesin Eg5 | volume = 286 | issue = 7 | pages = 5242–53 | year = 2011 | pmid = 21148480 | pmc = 3037637 | doi = 10.1074/jbc.M110.192930 | journal=Journal of Biological Chemistry}}</ref> but not yet been systematically explored. The initial goal of these mutation experiments was to determine which residues had greatest pharmacological importance in drug development.  For example, mutations in the KIF11 gene convey resistance of mitotic cell lines to inhibitors such as monastrol and STLC.<ref name="pmid20299460"/><ref name="pmid19896928">{{cite journal |vauthors=Tcherniuk S, van Lis R, Kozielski F, Skoufias DA | title = Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-L-cysteine in tumor derived cell lines | journal = Biochem. Pharmacol. | volume = 79 | issue = 6 | pages = 864–72 |date=March 2010 | pmid = 19896928 | doi = 10.1016/j.bcp.2009.11.001 }}</ref> 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.  In contrast to the loss-of-function experiments, a gain-of-function experiment using Drosophila Kinesin-5 showed that all L5-directed inhibitors do not allosterically communicate in the same way within the Kinesin-5 motor domain.<ref name="pmid21127071"/>  
 
A second purpose of mutational studies is to understand how drug resistance in cells is conferred from only changing one residue. These changes in the inhibitor-binding pocket are correlated with structural modification, or twist, of the central beta-sheet of the Kinesin-5 motor domain.<ref name="pmid20299460"/>  In this manner, the L5 loop may be able to directly control nucleotide binding and beta-sheet twist can manipulate the adjacent microtubule-binding site. This may explain how tumor cells rapidly can become drug-resistant to KIF11 inhibitors.

==Human Mutations==
KIF11 mutation have been wildly described in cancer and many trials with KIF11 inhibitor are ongoing.
{{Empty section|date=April 2013}}

==Mutations in MCLMR Syndrome==
Germline mutations in KIF11 cause Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation ([[MCLMR]]).<ref>{{OMIM|152950|MCLMR}}</ref> 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. Phenotypic evaluation of patients (n = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases. All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations.<ref name="Schlögel et al. ">{{cite journal |author1=Matthieu J Schlögel |author2=Antonella Mendola |author3=Elodie Fastré |author4=Pradeep Vasudevan |author5=Koen Devriendt |author6=Thomy JL de Ravel |author7=Hilde Van Esch |author8=Ingele Casteels |author9=Ignacio Arroyo Carrera |author10=Francesca Cristofoli |author11=Karen Fieggen |author12=Katheryn Jones |author13=Mark Lipson |author14=Irina Balikova |author15=Ami Singer |author16=Maria Soller |author17=María Mercedes Villanueva |author18=Nicole Revencu |author19=Laurence M Boon |author20=Pascal Brouillard |author21=Miikka Vikkula |date=May 2015 | title = No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome | journal =   Orphanet Journal of Rare Diseases | volume = 10 | issue = 52 | pages =  | publisher = BioMed Central | doi = 10.1186/s13023-015-0271-4 | pmid = 25934493 | pmc = 4464120| url = http://www.ojrd.com/content/10/1/52/abstract }}</ref>

==Notes==

{{Academic-written review
| wikidate = 2013
| journal = [[Gene (journal)|Gene]]
| title   = {{#property:P1476|from=Q21710690}}
| authors = {{#property:P2093|from=Q21710690}}
| date    = {{#property:P577|from=Q21710690}}
| volume  = {{#property:P478|from=Q21710690}}
| issue   = {{#property:P433|from=Q21710690}}
| pages   = {{#property:P304|from=Q21710690}}
| doi     = {{#property:P356|from=Q21710690}}
| pmid    = {{#property:P698|from=Q21710690}}
| pmc    = {{#property:P932|from=Q21710690}}
}}


==References==
 {{reflist|35em}}

==Further reading ==
 {{refbegin|35em}}
* {{cite journal |vauthors=Miki H, Setou M, Kaneshiro K, Hirokawa N | title = All kinesin superfamily protein, KIF, genes in mouse and human | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 13 | pages = 7004–11 |date=June 2001 | pmid = 11416179 | pmc = 34614 | doi = 10.1073/pnas.111145398 }}
* {{cite journal |vauthors=Prince JA, Feuk L, Gu HF, Johansson B, Gatz M, Blennow K, Brookes AJ | title = Genetic variation in a haplotype block spanning IDE influences Alzheimer disease | journal = Hum. Mutat. | volume = 22 | issue = 5 | pages = 363–71 |date=November 2003 | pmid = 14517947 | doi = 10.1002/humu.10282 }}
* {{cite journal |vauthors=Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J | title = N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso | journal = Mol. Cell | volume = 12 | issue = 3 | pages = 723–34 |date=September 2003 | pmid = 14527417 | doi = 10.1016/j.molcel.2003.08.008| url = }}
* {{cite journal |vauthors=Cassimeris L, Morabito J | title = TOGp, the human homolog of XMAP215/Dis1, is required for centrosome integrity, spindle pole organization, and bipolar spindle assembly | journal = Mol. Biol. Cell | volume = 15 | issue = 4 | pages = 1580–90 |date=April 2004 | pmid = 14718566 | pmc = 379257 | doi = 10.1091/mbc.E03-07-0544  }}
* {{cite journal |vauthors=Ertekin-Taner N, Allen M, Fadale D, Scanlin L, Younkin L, Petersen RC, Graff-Radford N, Younkin SG | title = Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease | journal = Hum. Mutat. | volume = 23 | issue = 4 | pages = 334–42 |date=April 2004 | pmid = 15024728 | doi = 10.1002/humu.20016 }}
* {{cite journal |vauthors=Tihy F, Kress M, Harper M, Dutrillaux B, Lemieux N | title = Localization of the human kinesin-related gene to band 10q24 by fluorescence in situ hybridization | journal = Genomics | volume = 13 | issue = 4 | pages = 1371–2 |date=August 1992 | pmid = 1505978 | doi = 10.1016/0888-7543(92)90075-4}}
* {{cite journal |vauthors=Cochran JC, Sontag CA, Maliga Z, Kapoor TM, Correia JJ, Gilbert SP | title = Mechanistic analysis of the mitotic kinesin Eg5 | journal = J. Biol. Chem. | volume = 279 | issue = 37 | pages = 38861–70 |date=September 2004 | pmid = 15247293 | pmc = 1356567 | doi = 10.1074/jbc.M404203200  }}
* {{cite journal |vauthors=Cochran JC, Gatial JE, Kapoor TM, Gilbert SP | title = Monastrol inhibition of the mitotic kinesin Eg5 | journal = J. Biol. Chem. | volume = 280 | issue = 13 | pages = 12658–67 |date=April 2005 | pmid = 15665380 | pmc = 1356610 | doi = 10.1074/jbc.M413140200 }}
* {{cite journal |vauthors=Feuk L, McCarthy S, Andersson B, Prince JA, Brookes AJ | title = Mutation screening of a haplotype block around the insulin degrading enzyme gene and association with Alzheimer's disease | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 136B | issue = 1 | pages = 69–71 |date=July 2005 | pmid = 15858821 | doi = 10.1002/ajmg.b.30172 }}
{{refend}}

== External links ==
* {{cite web|last=Baas|first=Peter|title=Peter Baas Laboratory|url=http://neurobio.mcphu.edu/BaasWeb/|work=Research Laboratory}}
* Block, Steven
* Gilbert, Susan
* Kapoor, Tarun
* Kim, Sunyoung
* Kozielski, Frank
* {{cite web|last=Mitchison|first=Tim|title=Tim Mitchison Laboratory|url=http://mitchison.med.harvard.edu/index.html|work=Mitchison Lab}}
* Moores, Carolyn
* Rice, Sarah
* Rosenfeld, Steven
* {{cite web|last=Wadsworth|first=Pat|title=Patricia Wadsworth Lab|url=http://www.bio.umass.edu/biology/wadsworth/|work=Research Lab}}
* Wojcik, Edward
* Worthylake, David
* {{cite web|last=Sharp|first=David|title=David Sharp Lab|url=http://www.einstein.yu.edu/faculty/7486/david-sharp/|work=Research Lab}}