Download Gene Section WWC1 (WW and C2 domain containing 1)

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Gene Section
Review
WWC1 (WW and C2 domain containing 1)
Lin Zhang, Jixin Dong
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center,
985950 Nebraska Medical Center, Omaha, NE 68198-5950, USA (LZ, JD)
Published in Atlas Database: August 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/WWC1ID45810ch5q34.html
DOI: 10.4267/2042/53533
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Pseudogene
Review on WWC1, with data on DNA/RNA, on the
protein encoded and where the gene is implicated.
No pseudogene of WWC1 is known.
Protein
Identity
Note
Preferred names: protein KIBRA
Names:
- protein KIBRA
- protein WWC1
- HBeAg-binding protein 3
- kidney and brain protein
- WW, C2 and coiled-coil domain containing 1
Other names: HBEBP3, HBEBP36, KIBRA
HGNC (Hugo): WWC1
Location: 5q34
DNA/RNA
Description
Description
The gene of WWC1 locates on chromosome 5q34,
with 23 exons crossing 180244bp (including untranslated regions) on the plus strand.
In total 137 single nucleotide polymorphisms are
present in ≥ 1% of samples according to UCSC
database.
KIBRA protein consists of 1119 amino acids
(isoform 1), with a predicted molecular weight of
125kDa. It was first cloned and identified as a
protein that interacts with the postsynaptic protein
dendrin (Kremerskothen et al., 2003). KIBRA is
constituted by two N-terminal WW domains, a C2
domain, a glutamic acid-rich domain and a PDZ
binding motif. The WW domains which contain
two conserved tryptophan residues are responsible
for recognizing PPxY motifs in various proteins
containing proline-rich sequences (PPxY).
Transcription
The open reading frame of mRNA contains 3360bp.
Three transcript variants encoding different
isoforms have been found for this gene (provided
by RefSeq, Mar 2010).
Diagram of WWC1 DNA which contains 23 exons shown with blue boxes.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4)
243
WWC1 (WW and C2 domain containing 1)
Zhang L, Dong J
Structure of human KIBRA. KIBRA contains two WW domains, a C2 domain, a glutamic acid-rich domain and a PDZ binding
motif.
The C2 domain located between amino acids 655
and 783 is implied to be involved in binding
phospholipids under assistance of two or three
calcium ions. In addition to the WW and C2
domain, a glutamic acid-rich region can be found
between amino acids 845 and 873 (Kremerskothen
et al., 2003; Rayala et al., 2006) and a PDZ-binding
motif is located between amino acids 1110 and
1113 at the C terminus (isoform 2) (Duning et al.,
2008). Further, a conserved motif containing serine
residue (Ser539) between the WW and C2 domains
of KIBRA, is phosphorylated and regulated by
aurora kinase and protein phosphatase 1 (Xiao et
al., 2011b). Recently, KIBRA Ser542 and Ser931
have been identified as main phosphorylation sites
for CDK1 (Ji et al., 2012).
In the field of neuroscience, KIBRA is associated
with
human
memory
performance
(Papassotiropoulos et al., 2006). The single
nucleotide polymorphism (SNP) of the ninth intron
of KIBRA gene, rs17070145, is associated with
human episodic memory performance. Carriers of
the T to C single nucleotide in the ninth intron have
better performance on episodic memory tasks
(Papassotiropoulos et al., 2006). After that, several
other groups also reported the association of
KIBRA with human memory performance in
different subject populations (Almeida et al., 2008;
Bates et al., 2009; Schaper et al., 2008). KIBRA
gene is also associated with Alzheimer's disease
and recurrent depressive disorders (Corneveaux et
al., 2010; Galecki et al., 2010). Besides, KIBRA
interacts with PKCzeta, which is involved in
synaptic plasticity (Büther et al.,2004).
Three recent studies independently identified
KIBRA in Drosophila as a tumor suppressor that
regulates Hippo signaling pathway, which controls
tissue growth and organ size (Baumgartner et al.,
2010; Genevet et al., 2010; Yu et al., 2010). This
function of KIBRA seems to be conserved in
mammals. Loss of KIBRA expression in
immortalized breast epithelial cells exhibits
epithelial-to-mesenchymal
transition
(EMT)
features and reduced expression of KIBRA in breast
cancer specimens correlates with poor prognosis
(Moleirinho et al., 2013). However, a recent study
reported that overexpression of KIBRA in gastric
cancer correlates with lymphatic invasion and poor
prognosis (Yoshihama et al., 2013). In podocytes,
KIBRA interacts with PATJ and synaptopodin and
positively modulates directional cell migration
(Duning et al., 2008). Methylation status of KIBRA
is correlated with prognosis of chronic lymphocytic
leukemia and specific genetic event in B-cell acute
lymphocytic leukemia (Shinawi et al., 2012; Hill et
al., 2011). KIBRA also plays an important role in
mitosis. KIBRA interacts with and regulates mitotic
kinase aurora and is required for precise mitotic
spindle assembly and chromosome alignment (Xiao
et al., 2011b; Zhang et al., 2012). Additionally,
KIBRA is also regulated by cyclin-dependent
kinase 1 (CDK1) and cell division cycle 14A/B
phosphatases (CDC14A, CDC14B) and thus
regulates cell-cycle progression (Ji et al., 2012).
Expression
KIBRA is predominately expressed in human
kidney and brain (Kremerskothen et al., 2003).
Gene expression studies and immunohistological
staining have shown that KIBRA is mainly
expressed in memory-related regions of the brain,
such as hippocampus and cortex (Papassotiropoulos
et al., 2006; Johannsen et al., 2008). In kidney,
KIBRA is expressed in glomerular podocytes,
tubules and some collecting ducts (Duning et al.,
2008). KIBRA can also be detected in heart and
colon.
Localisation
The localization of endogenously expressed
KIBRA depends on the cell type. KIBRA localizes
in the apical domain and at cell junctions in
epithelial cells (Yoshihama et al., 2011). In brain,
KIBRA co-localizes with protein kinase Mzeta
(PKMzeta) in the mouse hippocampus (Yoshihama
et al., 2009). In mouse kidney, KIBRA localizes in
the distal tubular epithelial cells (Yoshihama et al.,
2011). In migrating cells, KIBRA accumulates in
the leading edge (Duning et al., 2008).
Function
KIBRA is a cytoplasmatic protein that is involved
in various cellular processes and regulates a variety
of cellular functions such as cell growth and
apoptosis, directional cell migration, mitotic spindle
assembly and mitogen-activated protein kinase
(MAPK) activation.
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4)
244
WWC1 (WW and C2 domain containing 1)
Zhang L, Dong J
Homology
Epithelial-mesenchymal transition
The KIBRA gene is conserved in chimpanzee,
Rhesus monkey, dog, cow, mouse, rat, chicken,
zebrafish, fruit fly, and mosquito (Provided by
Pubmed). Two parologs of KIBRA have been
discovered in human: WWC2 and WWC3. One
ortholog of KIBRA (Kibra) has been identified in
Drosophila. KIBRA and WWC3 exist in fish, and
KIBRA and WWC2 are present in mice.
Note
Loss of KIBRA expression induces features of
epithelial-to-mesenchymal transition (EMT) in
mammary epithelial cells.
Decreased expression of KIBRA in breast cancer
specimens correlates with poor prognosis
(Moleirinho et al., 2013).
Mutations
Note
The single nucleotide polymorphism (SNP) of the
ninth intron of KIBRA gene, rs17070145, is
associated with human episodic memory
performance (Papassotiropoulos et al., 2006). A
recent study using KIBRA-knockout mice showed
that KIBRA is necessary for the contextual and
trace fear memory in adult mice (Makuch et al.,
2011). KIBRA is also associated with Alzheimer's
disease and recurrent depressive disorders
(Corneveaux et al., 2008; Galecki et al., 2010).
Memory performance
Note
No mutations of WWC1 are known.
Implicated in
Various cancers
Note
Genetic studies have identified Kibra as a tumor
suppressor in Drosophila. Kibra functions together
with Merlin and Expanded to regulate Hippo
signaling pathway, which controls tissue growth
and organ size (Baumgartner et al., 2010; Genevet
et al., 2010; Yu et al., 2010). This function of
KIBRA is also conserved in mammals. Methylation
status of KIBRA is correlated with prognosis of
chronic lymphocytic leukemia and specific genetic
event in B-cell acute lymphocytic leukemia
(Shinawi et al., 2012; Hill et al., 2011).
References
Kremerskothen J, Plaas C, Büther K, Finger I, Veltel S,
Matanis T, Liedtke T, Barnekow A. Characterization of
KIBRA, a novel WW domain-containing protein. Biochem
Biophys Res Commun. 2003 Jan 24;300(4):862-7
Büther K, Plaas C, Barnekow A, Kremerskothen J. KIBRA
is a novel substrate for protein kinase Czeta. Biochem
Biophys Res Commun. 2004 May 7;317(3):703-7
Papassotiropoulos A, Stephan DA, Huentelman MJ,
Hoerndli FJ, Craig DW, Pearson JV, Huynh KD, Brunner F,
Corneveaux J, Osborne D, Wollmer MA, Aerni A, Coluccia
D, Hänggi J, Mondadori CR, Buchmann A, Reiman EM,
Caselli RJ, Henke K, de Quervain DJ. Common Kibra
alleles are associated with human memory performance.
Science. 2006 Oct 20;314(5798):475-8
Cell cycle
Note
KIBRA is regulated by cyclin-dependent kinase 1
(CDK1) and cell division cycle 14A/B
phosphatases (CDC14) and thus regulates cell-cycle
progression (Ji et al., 2012). Besides, KIBRA
interacts and regulates mitotic kinase aurora during
mitosis and is required for precise mitotic spindle
assembly and chromosome alignment (Xiao et al.,
2011; Zhang et al., 2012).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4)
Rayala SK, den Hollander P, Manavathi B, Talukder AH,
Song C, Peng S, Barnekow A, Kremerskothen J, Kumar R.
Essential role of KIBRA in co-activator function of dynein
light chain 1 in mammalian cells. J Biol Chem. 2006 Jul
14;281(28):19092-9
245
WWC1 (WW and C2 domain containing 1)
Zhang L, Dong J
Almeida OP, Schwab SG, Lautenschlager NT, Morar B,
Greenop KR, Flicker L, Wildenauer D. KIBRA genetic
polymorphism influences episodic memory in later life, but
does not increase the risk of mild cognitive impairment. J
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the Salvador/Warts/Hippo (SWH) tumor suppressor
network, is associated with specific genetic event in B-cell
acute
lymphocytic
leukemia.
Epigenetics.
2011
Mar;6(3):326-32
Makuch L, Volk L, Anggono V, Johnson RC, Yu Y, Duning
K, Kremerskothen J, Xia J, Takamiya K, Huganir RL.
Regulation of AMPA receptor function by the human
memory-associated gene KIBRA. Neuron. 2011 Sep
22;71(6):1022-9
Duning K, Schurek EM, Schlüter M, Bayer M, Reinhardt
HC, Schwab A, Schaefer L, Benzing T, Schermer B,
Saleem MA, Huber TB, Bachmann S, Kremerskothen J,
Weide T, Pavenstädt H. KIBRA modulates directional
migration of podocytes. J Am Soc Nephrol. 2008
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Xiao L, Chen Y, Ji M, Dong J. KIBRA regulates Hippo
signaling activity via interactions with large tumor
suppressor kinases. J Biol Chem. 2011a Mar
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Johannsen S, Duning K, Pavenstädt H, Kremerskothen J,
Boeckers TM. Temporal-spatial expression and novel
biochemical properties of the memory-related protein
KIBRA. Neuroscience. 2008 Sep 9;155(4):1165-73
Xiao L, Chen Y, Ji M, Volle DJ, Lewis RE, Tsai MY, Dong
J. KIBRA protein phosphorylation is regulated by mitotic
kinase aurora and protein phosphatase 1. J Biol Chem.
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Schaper K, Kolsch H, Popp J, Wagner M, Jessen F.
KIBRA gene variants are associated with episodic memory
in healthy elderly. Neurobiol Aging. 2008 Jul;29(7):1123-5
Bates TC, Price JF, Harris SE, Marioni RE, Fowkes FG,
Stewart MC, Murray GD, Whalley LJ, Starr JM, Deary IJ.
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suppresses apical exocytosis through inhibition of aPKC
kinase activity in epithelial cells. Curr Biol. 2011 Apr
26;21(8):705-11
Yoshihama Y, Hirai T, Ohtsuka T, Chida K. KIBRA Colocalizes with protein kinase Mzeta (PKMzeta) in the
mouse hippocampus. Biosci Biotechnol Biochem. 2009
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Ji M, Yang S, Chen Y, Xiao L, Zhang L, Dong J. Phosphoregulation of KIBRA by CDK1 and CDC14 phosphatase
controls cell-cycle progression. Biochem J. 2012 Oct
1;447(1):93-102
Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker
H. The WW domain protein Kibra acts upstream of Hippo
in Drosophila. Dev Cell. 2010 Feb 16;18(2):309-16
Shinawi T, Hill V, Dagklis A, Baliakas P, Stamatopoulos K,
Agathanggelou A, Stankovic T, Maher ER, Ghia P, Latif F.
KIBRA gene methylation is associated with unfavorable
biological prognostic parameters in chronic lymphocytic
leukemia. Epigenetics. 2012 Mar;7(3):211-5
Corneveaux JJ, Liang WS, Reiman EM, Webster JA,
Myers AJ, Zismann VL, Joshipura KD, Pearson JV, HuLince D, Craig DW, Coon KD, Dunckley T, Bandy D, Lee
W, Chen K, Beach TG, Mastroeni D, Grover A, Ravid R,
Sando SB, Aasly JO, Heun R, Jessen F, Kölsch H, Rogers
J, Hutton ML, Melquist S, Petersen RC, Alexander GE,
Caselli RJ, Papassotiropoulos A, Stephan DA, Huentelman
MJ. Evidence for an association between KIBRA and lateonset Alzheimer's disease. Neurobiol Aging. 2010
Jun;31(6):901-9
Zhang L, Iyer J, Chowdhury A, Ji M, Xiao L, Yang S, Chen
Y, Tsai MY, Dong J. KIBRA regulates aurora kinase
activity and is required for precise chromosome alignment
during mitosis. J Biol Chem. 2012 Oct 5;287(41):34069-77
Moleirinho S, Chang N, Sims AH, Tilston-Lünel AM, Angus
L, Steele A, Boswell V, Barnett SC, Ormandy C, Faratian
D, Gunn-Moore FJ, Reynolds PA. KIBRA exhibits MSTindependent functional regulation of the Hippo signaling
pathway in mammals. Oncogene. 2013 Apr 4;32(14):182130
Galecki P, Szemraj J, Florkowski A, Talarowska M,
Bienkiewicz M, Galecka E, Lewinski A. Single nucleotide
polymorphism of the KIBRA gene in recurrent depressive
disorders. Neuro Endocrinol Lett. 2010;31(1):97-102
Yoshihama Y, Izumisawa Y, Akimoto K, Satoh Y,
Mizushima T, Satoh K, Chida K, Takagawa R, Akiyama H,
Ichikawa Y, Kunisaki C, Inayama Y, Endo I, Nagashima Y,
Ohno S. High expression of KIBRA in low atypical protein
kinase C-expressing gastric cancer correlates with
lymphatic invasion and poor prognosis. Cancer Sci. 2013
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Kibra is a regulator of the Salvador/Warts/Hippo signaling
network. Dev Cell. 2010 Feb 16;18(2):300-8
Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. Kibra
functions as a tumor suppressor protein that regulates
Hippo signaling in conjunction with Merlin and Expanded.
Dev Cell. 2010 Feb 16;18(2):288-99
This article should be referenced as such:
Zhang L, Dong J. WWC1 (WW and C2 domain containing
1). Atlas Genet Cytogenet Oncol Haematol. 2014;
18(4):243-246.
Hill VK, Dunwell TL, Catchpoole D, Krex D, Brini AT,
Griffiths M, Craddock C, Maher ER, Latif F. Frequent
epigenetic inactivation of KIBRA, an upstream member of
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4)
246