Alternative titles; symbols
HGNC Approved Gene Symbol: KIF15
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:44,761,794-44,868,687 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | ?Braddock-Carey syndrome 2 | 619981 | Autosomal recessive | 3 |
KIF15 is a molecular motor that participates in bipolar spindle assembly and centrosome separation during metaphase (Tanenbaum et al., 2009).
Using the N-terminal forkhead-associated domain of KI67 (MKI67; 176741) as bait in a yeast 2-hybrid screen of a HeLa cell cDNA library, Sueishi et al. (2000) cloned KIF15, which they called KLP2. The deduced 1,388-amino acid protein has an N-terminal kinesin-like motor domain, followed by a coiled-coil region and a C-terminal leucine zipper motif. KLP2 shares 53% amino acid identity with Xenopus Klp2. Immunohistochemical analysis of mitotic HeLa cells showed localization of KLP2 to centrosomes in interphase and primarily on mitotic spindles emanating from spindle poles during prometaphase to metaphase. At anaphase, KLP2 localized to equatorial region of spindles in a punctate pattern. Western blot analysis of mitotic HeLa cell extract detected KLP2 at an apparent molecular mass of 160 kD.
Eskova et al. (2014) found that fluorescence-tagged KIF15 localized to cytoplasm, with occasional localization to the plasma membrane, punctate cytoplasmic structures, and microtubules, in human cells.
Using data from the BrainSpan developmental transcriptome, Sleiman et al. (2017) observed expression of KIF15 across multiple regions prenatally, starting at 8 weeks postconception and tapering off 1 month postpartum. Using BioGPS data, the authors also detected expression in hematopoietic cells, including CD34+ and CD105+ cells.
Hartz (2017) mapped the KIF15 gene to chromosome 3p21.31 based on an alignment of the KIF15 sequence (GenBank AB035898) with the genomic sequence (GRCh38).
Klejnot et al. (2014) presented the crystal structure of the KIF15 motor domain and linker region at 2.7-angstrom resolution. The KIF15 motor domain showed a typical kinesin fold with an 8-stranded beta sheet surrounded by 3 major alpha helices on each side. In the presence of a slowly hydrolyzable ATP analog, KIF15 showed comparable affinity for alpha-tubulin (see 602529) and beta-tubulin (TUBB; 191130), suggesting that 1 KIF15 motor domain binds to 1 alpha- and beta-tubulin heterodimer.
Using recombinant proteins in an in vitro-binding assay, Sueishi et al. (2000) confirmed that KLP2 interacted with the forkhead-associated domain of KI67. Mutation analysis showed that a domain near the C terminus of KLP2 interacted with KI67. Synchronized mitotic HeLa cell extracts caused phosphorylation of this region of KLP2, suggesting that phosphorylated KLP2 interacts with KI67. Disruption of mitotic spindles resulted in relocalization of chromatin-associated KLP2 to dots on mitotic chromosomes. Sueishi et al. (2000) noted that Xenopus Klp2 is a plus-end-directed kinesin-like motor required for centrosome separation and maintenance of spindle bipolarity in mitotic Xenopus egg extracts.
Bipolar spindle assembly is driven by the microtubule motor EG5 (KIF11; 148760), which can slide antiparallel microtubules apart to drive centrosome separation. Using HeLa and U2OS human osteosarcoma cells, Tanenbaum et al. (2009) found that, although KIF15 was not essential for spindle assembly in the presence of EG5, overexpression of KIF15 restored most spindle assembly functions in the absence of EG5 activity. KIF15 failed to separate centrosomes in prophase in EG5-inhibited U2OS cells, suggesting that KIF15 specifically functions after nuclear envelope breakdown and that KIF15 cannot replicate early phases of EG5-dependent centrosome separation. Tanenbaum et al. (2009) found that the C-terminal leucine zipper of KIF15 bound to TPX2 (605917), and that depletion of TPX2 prevented KIF15 from binding to spindles and driving bipolar spindle assembly in the absence of EG5. Tanenbaum et al. (2009) proposed that a complex of KIF15 and TPX2 can crosslink and slide 2 antiparallel microtubules apart to drive centrosome separation, but only after initial EG5-dependent centrosome separation in prophase.
Using RNA interference assays in human cells, Eskova et al. (2014) showed that KIF15 was involved in internalization of alpha-2 integrin (ITGA2; 192974).
Klejnot et al. (2014) found that human KIF15 showed microtubule-stimulated ATPase activity. Knockdown of Kif15 in cultured rat cerebellar neurons resulted in inconsistent and stochastic neuronal migration.
Sturgill et al. (2016) identified a spontaneous EG5 mutant in HeLa cells that tightly bound microtubules regardless of its nucleotide state and/or pharmacologic inhibition. This EG5 rigor mutant activated KIF15-dependent spindle assembly by creating microtubule bundles, the preferred substrate of KIF15. Furthermore, KIF15 was essential for resistance to EG5 inhibitors and maintenance of mitotic progression in HeLa cells.
In a 2-year-old Saudi Arabian girl with Braddock-Carey syndrome-2 (BRDCS2; 619981), who had congenital thrombocytopenia, microcephaly, and Pierre-Robin sequence, Sleiman et al. (2017) identified homozygosity for a nonsense mutation in the KIF15 gene (R501X; 617569.0001). The mutation segregated with disease in the family and was not found in public variant databases. Experiments in cell lines derived from the proband demonstrated loss of KIF15 function with the variant.
In a 2-year-old Saudi Arabian girl with Braddock-Carey syndrome-2 (BRDCS2; 619981), who had congenital thrombocytopenia, microcephaly, and Pierre-Robin sequence, Sleiman et al. (2017) identified homozygosity for a c.1501C-T transition (c.1501C-T, NM_020242.2) in the KIF15 gene, resulting in an arg501-to-ter (R501X) substitution with truncation of the kinesin-like domain (KLP2) as well as the stalk and TPX2 (605917)-binding C terminus that encodes the hyaluronan-mediated motility receptor (HMMR; 600936). The unaffected consanguineous parents and an unaffected sib were heterozygous for the mutation, which was not found in 2 other unaffected sibs or in the NHLBI ESP or ExAC databases. Experiments in cell lines derived from the proband demonstrated greater inhibition of bipolar-spindle formation after EG5 (KIF11; 148760) inhibition by STLC compared to control cells, indicating loss of KIF15 function with the variant.
Eskova, A., Knapp, B., Matelska, D., Reusing, S., Arjonen, A., Lisauskas, T., Pepperkok, R., Russell, R., Eils, R., Ivaska, J., Kaderali, L., Erfle, H., Starkuviene, V. An RNAi screen identifies KIF15 as a novel regulator of the endocytic trafficking of integrin. J. Cell Sci. 127: 2433-2447, 2014. [PubMed: 24659801] [Full Text: https://doi.org/10.1242/jcs.137281]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/12/2017.
Klejnot, M., Falnikar, A., Ulaganathan, V., Cross, R. A., Baas, P. W., Kozielski, F. The crystal structure and biochemical characterization of Kif15: a bifunctional molecular motor involved in bipolar spindle formation and neuronal development. Acta Crystallogr. D Biol. Crystallogr. 70: 123-133, 2014. [PubMed: 24419385] [Full Text: https://doi.org/10.1107/S1399004713028721]
Sleiman, P. M. A., March, M., Nguyen, K., Tian, L., Pellegrino, R., Hou, C., Dridi, W., Sager, M., Housawi, Y. H., Hakonarson, H. Loss-of-function mutations in KIF15 underlying a Braddock-Carey genocopy. Hum. Mutat. 38: 507-510, 2017. [PubMed: 28150392] [Full Text: https://doi.org/10.1002/humu.23188]
Sturgill, E. G., Norris, S. R., Guo, Y., Ohi, R. Kinesin-5 inhibitor resistance is driven by kinesin-12. J. Cell Biol. 213: 213-227, 2016. [PubMed: 27091450] [Full Text: https://doi.org/10.1083/jcb.201507036]
Sueishi, M., Takagi, M., Yoneda, Y. The forkhead-associated domain of Ki-67 antigen interacts with the novel kinesin-like protein Hklp2. J. Biol. Chem. 275: 28888-28892, 2000. [PubMed: 10878014] [Full Text: https://doi.org/10.1074/jbc.M003879200]
Tanenbaum, M. E., Macurek, L., Janssen, A., Geers, E. F., Alvarez-Fernandez, M., Medema, R. H. Kif15 cooperates with Eg5 to promote bipolar spindle assembly. Curr. Biol. 19: 1703-1711, 2009. [PubMed: 19818618] [Full Text: https://doi.org/10.1016/j.cub.2009.08.027]