Kinesin family member 11

1II6, 1Q0B, 1X88, 1YRS, 2FKY, 2FL2, 2FL6, 2FME, 2G1Q, 2GM1, 2IEH, 2PG2, 2Q2Y, 2Q2Z, 2UYI, 2UYM, 2WOG, 2X2R, 2X7C, 2X7D, 2X7E, 2XAE, 3CJO, 3HQD, 3K3B, 3K5E, 3KEN, 3L9H, 3WPN, 3ZCW, 4A1Z, 4A28, 4A50, 4A51, 4A5Y, 4AP0, 4AQV, 4AQW, 4AS7, 4B7B, 4BBG, 4BXN, 4CK5, 4CK6, 4CK7, 4ZCA, 4ZHI383216551ENSG00000138160ENSMUSG00000012443P52732Q6P9P6NM_004523NM_010615NP_004514NP_034745Kinesin-5 is a molecular motor protein that is essential in mitosis. 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, 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. Kinesin-5 is a molecular motor protein that is essential in mitosis. 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, 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 dynamics and essential for mitosis. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. The human Kinesin-5 protein has been actively studied for its role in mitosis and its potential as a therapeutic target for cancer treatment. 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. 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. 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. 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. 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. 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. 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. This toolkit of allosteric inhibitors has been used to probe the specific role of Kinesin-5 in mitotic spindle assembly as well as fine dissection of motor domain function. 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. 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. 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. 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. 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. Among non-dividing cells, Kinesin-5 is most enriched within neurons, wherein it decorates the large microtubule bundles extending into axons and dendrites. 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. In migratory neurons, inhibition of KIF11 causes neurons to migrate in a random pattern and form shorter leading processes. 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. In mature neurons, KIF11 restricts the movement of short microtubules in dendrites, contributing to the formation of characteristic shape of dendrites. 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. 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. In 1995, Kinesin-5 was determined to be post-translationally phosphorylated within its C-terminal tail. 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. While additional phosphosites or other post-translational modifications within the Kinesin-5 tail, stalk, and motor have been identified, no other modifications have been proven as necessary for Kinesin-5 to perform its necessary tasks in mitosis.