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KIF14 (kinesin family member 14)
Brigitte L Thériault, Timothy W Corson
Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University
Health Network, Toronto, ON, Canada (BLT), Eugene & Marilyn Glick Eye Institute, Department of
Ophthalmology, and Department of Biochemistry and Molecular Biology, Indiana University School of
Medicine, USA (TWC)
Published in Atlas Database: April 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/KIF14ID44138ch1q32.html
DOI: 10.4267/2042/48141
This article is an update of :
Thériault BL, Corson TW. KIF14 (kinesin family member 14). Atlas Genet Cytogenet Oncol Haematol 2008;12(4):311-313.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DNA/RNA
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 Nterminal extension in KIF14 is unique in this family.
High-throughput
studies
have
identified
phosphorylations on Ser-12, Tyr-196, Thr-240, Ser242, 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).
Description
Expression
Gene spans 68,5 kbp on the minus strand at 1q32.1.
One known 6586 base transcript, 30 exons.
The KIF14 promoter is bound by p130/E2F4 under
growth arrest conditions (Cam et al., 2004); further
details of transcriptional regulation are currently
lacking.
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).
Pseudogene
Localisation
None annotated.
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).
Identity
Other names: KIAA0042
HGNC (Hugo): KIF14
Location: 1q32.1
Local order: Genes flanking KIF14 at 1q32.1 are
(centromeric to telomeric): ZNF281 (zinc finger protein
281), KIF14, DDX59 (DEAD (Asp-Glu-Ala-Asp) box
polypeptide 59).
Transcription
Protein
Description
KIF14 is a 186 kDa, 1648 aa protein, containing
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
695
KIF14 (kinesin family member 14)
Thériault BL, Corson TW
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 Cterminal 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 Cterminal 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 Cterminal 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).
Function
Somatic
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).
Missense somatic mutations were detected in two
metastatic
melanomas.
Each
mutations
was
heterozygous and observed in a single tumor. They
were c.1490 C>T, P351S and c.1539 C>T, P367L (Wei
et al., 2011).
Heterozygous somatic mutations were detected in five
breast ductal carcinoma tumors. Each mutation was
observed in a single tumor and included three missense
mutations (c.3676T>A, p.S1226T; c.4363G>C,
p.E1455Q and c.1A>G, p.M1V), one synonymous
mutation (c.4539T>A, p.A1513A), and one nonsense
mutation (c.4402G>T, p.E1468*) (Wood et al., 2007).
Missense heterozygous somatic mutations were
detected in two ovarian carcinomas and each mutation
was observed in a single tumor: c.2096G>A, p.R699H
and c.4654C>T, p.P1552S (Cancer Genome Atlas
Research Network, 2011).
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).
Implicated in
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).
Mutations
Germinal
None yet identified.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
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KIF14 (kinesin family member 14)
Thériault BL, Corson TW
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).
Cytogenetics
KIF14 lies in a "hotspot" of genomic gain at 1q31.31q32.1 (Corson et al., 2005).
Low-level genomic gain (3-5 copies) of the gene is
observed in 50% of tumors (Bowles et al., 2007). Highlevel 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).
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).
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 1q31.31q32.1.
Low-level genomic gain of the gene is observed in 50%
of breast cancer cell lines (Bowles et al., 2007).
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).
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).
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).
Ovarian carcinoma
Glioblastoma multiforme
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).
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).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
Laryngeal carcinoma
Oncogenesis
KIF14 is one of three microarray-identified genes
validated as a marker of laryngeal carcinoma
(Markowski et al., 2009).
697
KIF14 (kinesin family member 14)
Thériault BL, Corson TW
Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB,
Gallie BL. Profiling genomic copy number changes in
retinoblastoma beyond loss of RB1. Genes Chromosomes
Cancer. 2007 Feb;46(2):118-29
To be noted
Note
Numerous microarray studies indexed in Oncomine
document overexpression of KIF14 in other cancers,
including brain tumors, seminoma, prostate and tongue
cancers.
Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS, Gallie
BL. KIF14 messenger RNA expression is independently
prognostic for outcome in lung cancer. Clin Cancer Res. 2007
Jun 1;13(11):3229-34
Madhavan J, Coral K, Mallikarjuna K, Corson TW, Amit N,
Khetan V, George R, Biswas J, Gallie BL, Kumaramanickavel
G. High expression of KIF14 in retinoblastoma: association
with older age at diagnosis. Invest Ophthalmol Vis Sci. 2007
Nov;48(11):4901-6
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This article should be referenced as such:
Thériault BL, Corson TW. KIF14 (kinesin family member 14).
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