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| | Schematic representation of the KIF14 protein (not to scale). KIF14 contains two major effector domains. The first is a highly conserved 274 aa kinesin motor domain containing an ATP-binding site (aa 447-454) which is involved in microtubule-dependent ATPase activity, and a microtubule binding site (aa 455-628) involved in ATP-dependent protein transport. The second is a 67 aa forkhead-associated (FHA) domain (aa 825-891) which has similarity to the SMAD Mad Homology 2 (MH2) domain, and is involved in mediating protein-protein interactions with phosphoproteins, although no such interactions have been documented for KIF14 (Durocher et al., 2000). In addition to the highly conserved N-type neck region (N) adjacent to the motor domain, KIF14 also contains four other C-terminal regions predicted to form coiled-coil structures (1-4). Phosphorylation sites have been identified in high-throughput studies on Ser-12, Tyr-196, Thr-240, Ser-242, Ser-378, Ser-384, Ser-670, Ser-1200, Ser-1292, Ser-1631, Ser-1636 and Thr-1641 (P) (Nomura et al., 1994; Olsen et al., 2006; Vasilescu et al., 2007; Dephoure et al., 2008), and a ubiquitination site identified on Lys-275 (U) (Olsen et al., 2006; Vasilescu et al., 2007). The kinesin motor and FHA domains are flanked by a 354 aa N-terminal extension, and a 758 aa C-terminal stalk and tail region. The N-terminal extension is involved in the binding of PRC1 (protein-regulating cytokinesis 1), a protein crucial for the proper formation of the central spindle structure during cytokinesis. Citron kinase has been shown to interact with the C-terminal stalk and tail of KIF14, and this interaction is required for proper localization of KIF14 to the mitotic spindle. Supervillin, a membrane protein involved in directing cellular motility, has been shown to associate directly with the distal C-terminal tail of KIF14 and contributes to the establishment or maintenance of the cytokinetic furrow (Smith et al., 2010). |
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| Description | KIF14 is a 186 kDa, 1648 aa protein, containing kinesin motor and forkhead-associated (FHA) domains. It is a member of the N-3 family of kinesins, in which the motor domain lies close to the amino terminus (Miki et al., 2001), although the relatively long N-terminal extension in KIF14 is unique in this family. High-throughput studies have identified phosphorylations on Ser-12, Tyr-196, Thr-240, Ser-242, Ser-378, Ser-384, Ser-670, Ser-1200, Ser-1292, Ser-1631, Ser-1636 and Thr-1641 (P) (Nomura et al., 1994; Olsen et al., 2006; Vasilescu et al., 2007; Dephoure et al., 2008), and ubiquitination on Lys-275 (U) (Olsen et al., 2006; Vasilescu et al., 2007). |
| Expression | KIF14 was cloned from an immature myeloid cell line, KG-1 (Nomura et al., 1994). By qRT-PCR, KIF14 is expressed at low levels in normal adult tissues and at higher levels in placenta and fetal tissues; highest expression is in fetal thymus and liver (Corson et al., 2005). KIF14 expression varies with the cell cycle, with highest expression at G2-M (Carleton et al., 2006). |
| Localisation | In HeLa cells, KIF14 is localized to the cytoplasm during interphase, and becomes tightly localized to the midbody and central spindle during cytokinesis (Carleton et al., 2006; Gruneberg et al., 2006). |
| Function | KIF14 is a mitotic kinesin motor protein with ATPase activity (Carleton et al., 2006). It interacts with protein regulator of cytokinesis 1 (PRC1) and is essential for localizing citron kinase to the mitotic spindle (Gruneberg et al., 2006). KIF14 knockdown results in failure of cytokinesis, leading to multinucleation and/or apoptosis, but no chromosome segregation defects (Carleton et al., 2006; Gruneberg et al., 2006). KIF14 also interacts with supervillin and contributes to the establishment or maintenance of the cytokinetic furrow (Smith et al., 2010). In addition, KIF14 was identified as a β-arrestin 2 interacting protein in the nucleus of mature spermatozoa (Neuhaus et al., 2006). |
| Homology | There are KIF14 orthologs in several mammalian species. The closest Drosophila melanogaster gene, with 40% amino acid identity, is nebbish/tiovivo, encoding Klp38B (kinesin-like protein 38B). Klp38B is a mitotic kinesin that binds to chromatin and microtubules in the formation of the bipolar spindle and attachment of chromosomes to the spindle, and/or acts in cytokinesis (Molina et al., 1997; Ohkura et al., 1997). |
| Entity | Retinoblastoma |
| Prognosis | KIF14 mRNA and protein expression is greatly increased in retinoblastoma tumors versus normal adult and fetal retina (Corson et al., 2005). mRNA expression is higher in older patients' tumors than younger (Madhavan et al., 2007), and shows a modest association with unilateral disease (Madhavan et al., 2009). KIF14 mRNA level increases with the progression from normal retina to benign retinoma to retinoblastoma (Dimaras et al., 2008). |
| Cytogenetics | KIF14 lies in a "hotspot" of genomic gain at 1q31.3-1q32.1 (Corson et al., 2005). Low-level genomic gain (3-5 copies) of the gene is observed in 50% of tumors (Bowles et al., 2007). High-level amplification has been observed in one tumor (along with, but independent of, MYCN amplification) (Bowles et al., 2007). KIF14 copy number increases during the progression from normal retina to benign retinoma to retinoblastoma (Dimaras et al., 2008). |
| Oncogenesis | In support of KIF14's importance in retinoblastoma, the mouse ortholog Kif14 is expressed in retinal tumors in the retinal SV40 Large T Antigen (TAg-RB) model of retinoblastoma at levels higher than at any point in mouse retinal development (Pajovic et al., 2011). |
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| Entity | Breast carcinoma |
| Prognosis | mRNA expression increases with grade, and is higher in ductal than lobular carcinoma, and in estrogen receptor (ER) negative over ER positive tumors. Expression correlates with proliferation, and overexpression is prognostic for poor overall and disease-free survival (Corson and Gallie, 2006). |
| Cytogenetics | KIF14 lies in a "hotspot" of genomic gain at 1q31.3-1q32.1. Low-level genomic gain of the gene is observed in 50% of breast cancer cell lines (Bowles et al., 2007). |
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| Entity | Non-small-cell lung carcinoma (NSCLC) |
| Prognosis | mRNA expression decreases with differentiation, and is higher in squamous cell than adenocarcinoma. Overexpression is independently prognostic for poor disease-free survival, and prognostic for poor overall survival (Corson et al., 2007). |
| Oncogenesis | Knockdown of KIF14 decreases proliferation of H1299 NSCLC cells, and decreases their ability to form colonies in soft agar (Corson et al., 2007). |
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| Entity | Ovarian carcinoma |
| Prognosis | KIF14 is overexpressed in the majority of ovarian cancers tested (91%). KIF14 mRNA expression is independently prognostic for poor overall survival and prognostic for poor progression-free survival in serous ovarian cancers (Thériault et al., 2012). |
| Cytogenetics | Low-level gain (3 to 5 copies) of KIF14 is observed in 30% of serous ovarian cancers, and corresponds to high mRNA overexpression (Thériault et al., 2012). KIF14 was the only gene within the documented 1q "hot spot" region of gain (1q31.3-1q32.1) (Corson et al., 2005) to be overexpressed in ovarian carcinomas compared to normal tubal epithelium and ovarian surface epithelium (Thériault et al., 2012). |
| Oncogenesis | Overexpression of KIF14 enhances proliferation, and in vitro tumorigenic potential in ovarian cancer cell lines. Knockdown significantly reduces in vitro proliferation and tumorigenicity, and induces an apoptotic response (Thériault et al., 2012). |
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| Entity | Hepatocellular carcinoma (HCC) |
| Prognosis | KIF14 is overexpressed in HCC. |
| Cytogenetics | Low-level gain of the KIF14 locus is seen in 58% tumors (Bowles et al., 2007). A KIF14-containing region spanning 1q32.1-1q44 was the second most common alteration in a series of HCC, and KIF14 mRNA and protein expression were increased in tumors with gain of this region (Kim et al., 2008). |
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| Entity | Pancreatic carcinoma |
| Prognosis | KIF14 was identified by expression microarray (and confirmed by RT-PCR and immunoblot) as downregulated in neuroinvasive versus non-invasive pancreatic carcinoma cell lines. However, KIF14 was upregulated in chronic pancreatitis and pancreatic cancer versus normal pancreas (Abiatari et al., 2009). |
| Oncogenesis | Knockdown of KIF14 increased invasiveness of T3M4 cells and also increased resistance to anoikis of these cells (Abiatari et al., 2009). |
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| Entity | Papillary renal cell tumors |
| Prognosis | Gain of a region of 1q including KIF14 is associated with fatal progression, and KIF14 is one of two genes overexpressed in tumors with this gain to a higher level than in tumors without 1q gain (Szponar et al., 2009). |
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| Entity | Glioblastoma multiforme |
| Cytogenetics | Two translocation breakpoints in a series of 32 tumors mapped to 1q32. KIF14 was identified as an overexpressed gene in a region of somatic gain around this breakpoint (Leone et al., 2012). |
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| Entity | Laryngeal carcinoma |
| Oncogenesis | KIF14 is one of three microarray-identified genes validated as a marker of laryngeal carcinoma (Markowski et al., 2009). |
| | |
| Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. |
| Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S. |
| DNA Res. 1994;1(5):223-9. |
| PMID 7584044 |
| |
| A chromatin-associated kinesin-related protein required for normal mitotic chromosome segregation in Drosophila. |
| Molina I, Baars S, Brill JA, Hales KG, Fuller MT, Ripoll P. |
| J Cell Biol. 1997 Dec 15;139(6):1361-71. |
| PMID 9396743 |
| |
| Mutation of a gene for a Drosophila kinesin-like protein, Klp38B, leads to failure of cytokinesis. |
| Ohkura H, Torok T, Tick G, Hoheisel J, Kiss I, Glover DM. |
| J Cell Sci. 1997 Apr;110 ( Pt 8):945-54. |
| PMID 9152020 |
| |
| The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. |
| Durocher D, Taylor IA, Sarbassova D, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB. |
| Mol Cell. 2000 Nov;6(5):1169-82. |
| PMID 11106755 |
| |
| All kinesin superfamily protein, KIF, genes in mouse and human. |
| Miki H, Setou M, Kaneshiro K, Hirokawa N. |
| Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7004-11. (REVIEW) |
| PMID 11416179 |
| |
| A common set of gene regulatory networks links metabolism and growth inhibition. |
| Cam H, Balciunaite E, Blais A, Spektor A, Scarpulla RC, Young R, Kluger Y, Dynlacht BD. |
| Mol Cell. 2004 Nov 5;16(3):399-411. |
| PMID 15525513 |
| |
| KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers. |
| Corson TW, Huang A, Tsao MS, Gallie BL. |
| Oncogene. 2005 Jul 14;24(30):4741-53. |
| PMID 15897902 |
| |
| Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. |
| Zhu C, Zhao J, Bibikova M, Leverson JD, Bossy-Wetzel E, Fan JB, Abraham RT, Jiang W. |
| Mol Biol Cell. 2005 Jul;16(7):3187-99. Epub 2005 Apr 20. |
| PMID 15843429 |
| |
| RNA interference-mediated silencing of mitotic kinesin KIF14 disrupts cell cycle progression and induces cytokinesis failure. |
| Carleton M, Mao M, Biery M, Warrener P, Kim S, Buser C, Marshall CG, Fernandes C, Annis J, Linsley PS. |
| Mol Cell Biol. 2006 May;26(10):3853-63. |
| PMID 16648480 |
| |
| KIF14 mRNA expression is a predictor of grade and outcome in breast cancer. |
| Corson TW, Gallie BL. |
| Int J Cancer. 2006 Sep 1;119(5):1088-94. |
| PMID 16570270 |
| |
| KIF14 and citron kinase act together to promote efficient cytokinesis. |
| Gruneberg U, Neef R, Li X, Chan EH, Chalamalasetty RB, Nigg EA, Barr FA. |
| J Cell Biol. 2006 Jan 30;172(3):363-72. Epub 2006 Jan 23. |
| PMID 16431929 |
| |
| Novel function of beta-arrestin2 in the nucleus of mature spermatozoa. |
| Neuhaus EM, Mashukova A, Barbour J, Wolters D, Hatt H. |
| J Cell Sci. 2006 Aug 1;119(Pt 15):3047-56. Epub 2006 Jul 4. |
| PMID 16820410 |
| |
| Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. |
| Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M. |
| Cell. 2006 Nov 3;127(3):635-48. |
| PMID 17081983 |
| |
| Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. |
| Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB, Gallie BL. |
| Genes Chromosomes Cancer. 2007 Feb;46(2):118-29. |
| PMID 17099872 |
| |
| KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. |
| Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS, Gallie BL. |
| Clin Cancer Res. 2007 Jun 1;13(11):3229-34. |
| PMID 17545527 |
| |
| High expression of KIF14 in retinoblastoma: association with older age at diagnosis. |
| Madhavan J, Coral K, Mallikarjuna K, Corson TW, Amit N, Khetan V, George R, Biswas J, Gallie BL, Kumaramanickavel G. |
| Invest Ophthalmol Vis Sci. 2007 Nov;48(11):4901-6. |
| PMID 17962437 |
| |
| The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: application for identifying ubiquitinated proteins in human cells. |
| Vasilescu J, Zweitzig DR, Denis NJ, Smith JC, Ethier M, Haines DS, Figeys D. |
| J Proteome Res. 2007 Jan;6(1):298-305. |
| PMID 17203973 |
| |
| The genomic landscapes of human breast and colorectal cancers. |
| Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B. |
| Science. 2007 Nov 16;318(5853):1108-13. Epub 2007 Oct 11. |
| PMID 17932254 |
| |
| A quantitative atlas of mitotic phosphorylation. |
| Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP. |
| Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. Epub 2008 Jul 31. |
| PMID 18669648 |
| |
| Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. |
| Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, Marrano P, Corson TW, Eagle RC Jr, Squire JA, Gallie BL. |
| Hum Mol Genet. 2008 May 15;17(10):1363-72. Epub 2008 Jan 22. |
| PMID 18211953 |
| |
| Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q. |
| Kim TM, Yim SH, Shin SH, Xu HD, Jung YC, Park CK, Choi JY, Park WS, Kwon MS, Fiegler H, Carter NP, Rhyu MG, Chung YJ. |
| Int J Cancer. 2008 Dec 15;123(12):2808-15. |
| PMID 18803288 |
| |
| Consensus transcriptome signature of perineural invasion in pancreatic carcinoma. |
| Abiatari I, DeOliveira T, Kerkadze V, Schwager C, Esposito I, Giese NA, Huber P, Bergman F, Abdollahi A, Friess H, Kleeff J. |
| Mol Cancer Ther. 2009 Jun;8(6):1494-504. Epub 2009 Jun 9. |
| PMID 19509238 |
| |
| KIF14 and E2F3 mRNA expression in human retinoblastoma and its phenotype association. |
| Madhavan J, Mitra M, Mallikarjuna K, Pranav O, Srinivasan R, Nagpal A, Venkatesan P, Kumaramanickavel G. |
| Mol Vis. 2009;15:235-40. Epub 2009 Jan 26. |
| PMID 19190782 |
| |
| Metal-proteinase ADAM12, kinesin 14 and checkpoint suppressor 1 as new molecular markers of laryngeal carcinoma. |
| Markowski J, Tyszkiewicz T, Jarzab M, Oczko-Wojciechowska M, Gierek T, Witkowska M, Paluch J, Kowalska M, Wygoda Z, Lange D, Jarzab B. |
| Eur Arch Otorhinolaryngol. 2009 Oct;266(10):1501-7. Epub 2009 Jul 16. |
| PMID 19609547 |
| |
| Three genetic developmental stages of papillary renal cell tumors: duplication of chromosome 1q marks fatal progression. |
| Szponar A, Zubakov D, Pawlak J, Jauch A, Kovacs G. |
| Int J Cancer. 2009 May 1;124(9):2071-6. |
| PMID 19123481 |
| |
| Novel interactors and a role for supervillin in early cytokinesis. |
| Smith TC, Fang Z, Luna EJ. |
| Cytoskeleton (Hoboken). 2010 Jun;67(6):346-64. |
| PMID 20309963 |
| |
| Integrated genomic analyses of ovarian carcinoma. |
| Cancer Genome Atlas Research Network. |
| Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166. |
| PMID 21720365 |
| |
| RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma. |
| Huang Q, Lin B, Liu H, Ma X, Mo F, Yu W, Li L, Li H, Tian T, Wu D, Shen F, Xing J, Chen ZN. |
| PLoS One. 2011;6(10):e26168. Epub 2011 Oct 17. |
| PMID 22043308 |
| |
| The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties. |
| Pajovic S, Corson TW, Spencer C, Dimaras H, Orlic-Milacic M, Marchong MN, To KH, Theriault B, Auspitz M, Gallie BL. |
| Invest Ophthalmol Vis Sci. 2011 Sep 29;52(10):7618-24. Print 2011 Sep. |
| PMID 21862643 |
| |
| Exome sequencing identifies GRIN2A as frequently mutated in melanoma. |
| Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S; NISC Comparative Sequencing Program, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y. |
| Nat Genet. 2011 May;43(5):442-6. Epub 2011 Apr 15. |
| PMID 21499247 |
| |
| Integration of global spectral karyotyping, CGH arrays, and expression arrays reveals important genes in the pathogenesis of glioblastoma multiforme. |
| Leone PE, Gonzalez MB, Elosua C, Gomez-Moreta JA, Lumbreras E, Robledo C, Santos-Briz A, Valero JM, de la Guardia RD, Gutierrez NC, Hernandez JM, Garcia JL. |
| Ann Surg Oncol. 2012 Jul;19(7):2367-79. Epub 2012 Mar 7. |
| PMID 22395973 |
| |
| Kinesin family member 14: an independent prognostic marker and potential therapeutic target for ovarian cancer. |
| Theriault BL, Pajovic S, Bernardini MQ, Shaw PA, Gallie BL. |
| Int J Cancer. 2012 Apr 15;130(8):1844-54. doi: 10.1002/ijc.26189. Epub 2011 Aug 5. |
| PMID 21618518 |
| |