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Gene Section Review Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST -CNRS 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 No pseudogene of WWC1 is known. protein encoded and where the gene is implicated. Protein Identity Note Other names: HBEBP3, HBEBP36, KIBRA Preferred names: protein KIBRA Names: HGNC (Hugo): WWC1 - protein KIBRA Location: 5q34 - protein WWC1 - HBeAg-binding protein 3 DNA/RNA - kidney and brain protein - WW, C2 and coiled-coil domain containing 1 Description Description The gene of WWC1 locates on chromosome 5q34, with 23 exons crossing 180244bp (including un- KIBRA protein consists of 1119 amino acids translated regions) on the plus strand. (isoform 1), with a predicted molecular weight of In total 137 single nucleotide polymorphisms are 125kDa. It was first cloned and identified as a present in ≥ 1% of samples according to UCSC protein that interacts with the postsynaptic protein database. dendrin (Kremerskothen et al., 2003). KIBRA is constituted by two N-terminal WW domains, a C2 Transcription domain, a glutamic acid-rich domain and a PDZ The open reading frame of mRNA contains 3360bp. binding motif. The WW domains which contain Three transcript variants encoding different two conserved tryptophan residues are responsible isoforms have been found for this gene (provided for recognizing PPxY motifs in various proteins by RefSeq, Mar 2010). containing proline-rich sequences (PPxY). 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 In the field of neuroscience, KIBRA is associated and 783 is implied to be involved in binding with human memory performance phospholipids under assistance of two or three (Papassotiropoulos et al., 2006). The single calcium ions. In addition to the WW and C2 nucleotide polymorphism (SNP) of the ninth intron domain, a glutamic acid-rich region can be found of KIBRA gene, rs17070145, is associated with between amino acids 845 and 873 (Kremerskothen human episodic memory performance. Carriers of et al., 2003; Rayala et al., 2006) and a PDZ-binding the T to C single nucleotide in the ninth intron have motif is located between amino acids 1110 and better performance on episodic memory tasks 1113 at the C terminus (isoform 2) (Duning et al., (Papassotiropoulos et al., 2006). After that, several 2008). Further, a conserved motif containing serine other groups also reported the association of residue (Ser539) between the WW and C2 domains KIBRA with human memory performance in of KIBRA, is phosphorylated and regulated by different subject populations (Almeida et al., 2008; aurora kinase and protein phosphatase 1 (Xiao et Bates et al., 2009; Schaper et al., 2008). KIBRA al., 2011b). Recently, KIBRA Ser542 and Ser931 gene is also associated with Alzheimer's disease have been identified as main phosphorylation sites and recurrent depressive disorders (Corneveaux et for CDK1 (Ji et al., 2012). al., 2010; Galecki et al., 2010). Besides, KIBRA Expression interacts with PKCzeta, which is involved in synaptic plasticity (Büther et al.,2004). KIBRA is predominately expressed in human Three recent studies independently identified kidney and brain (Kremerskothen et al., 2003). KIBRA in Drosophila as a tumor suppressor that Gene expression studies and immunohistological regulates Hippo signaling pathway, which controls staining have shown that KIBRA is mainly tissue growth and organ size (Baumgartner et al., expressed in memory-related regions of the brain, 2010; Genevet et al., 2010; Yu et al., 2010). This such as hippocampus and cortex (Papassotiropoulos function of KIBRA seems to be conserved in et al., 2006; Johannsen et al., 2008). In kidney, mammals. Loss of KIBRA expression in KIBRA is expressed in glomerular podocytes, immortalized breast epithelial cells exhibits tubules and some collecting ducts (Duning et al., epithelial-to-mesenchymal transition (EMT) 2008). KIBRA can also be detected in heart and features and reduced expression of KIBRA in breast colon. cancer specimens correlates with poor prognosis Localisation (Moleirinho et al., 2013). However, a recent study The localization of endogenously expressed reported that overexpression of KIBRA in gastric KIBRA depends on the cell type. KIBRA localizes cancer correlates with lymphatic invasion and poor in the apical domain and at cell junctions in prognosis (Yoshihama et al., 2013). In podocytes, epithelial cells (Yoshihama et al., 2011). In brain, KIBRA interacts with PATJ and synaptopodin and KIBRA co-localizes with protein kinase Mzeta positively modulates directional cell migration (PKMzeta) in the mouse hippocampus (Yoshihama (Duning et al., 2008). Methylation status of KIBRA et al., 2009). In mouse kidney, KIBRA localizes in is correlated with prognosis of chronic lymphocytic the distal tubular epithelial cells (Yoshihama et al., leukemia and specific genetic event in B-cell acute 2011). In migrating cells, KIBRA accumulates in lymphocytic leukemia (Shinawi et al., 2012; Hill et the leading edge (Duning et al., 2008). al., 2011). KIBRA also plays an important role in mitosis. KIBRA interacts with and regulates mitotic Function kinase aurora and is required for precise mitotic KIBRA is a cytoplasmatic protein that is involved spindle assembly and chromosome alignment (Xiao in various cellular processes and regulates a variety et al., 2011b; Zhang et al., 2012). Additionally, of cellular functions such as cell growth and KIBRA is also regulated by cyclin-dependent apoptosis, directional cell migration, mitotic spindle kinase 1 (CDK1) and cell division cycle 14A/B assembly and mitogen-activated protein kinase phosphatases (CDC14A, CDC14B) and thus (MAPK) activation. regulates cell-cycle progression (Ji et al., 2012). 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, Note Rhesus monkey, dog, cow, mouse, rat, chicken, Loss of KIBRA expression induces features of zebrafish, fruit fly, and mosquito (Provided by epithelial-to-mesenchymal transition (EMT) in Pubmed). Two parologs of KIBRA have been mammary epithelial cells. discovered in human: WWC2 and WWC3. One Decreased expression of KIBRA in breast cancer ortholog of KIBRA (Kibra) has been identified in specimens correlates with poor prognosis Drosophila. KIBRA and WWC3 exist in fish, and (Moleirinho et al., 2013). KIBRA and WWC2 are present in mice. Memory performance Mutations Note The single nucleotide polymorphism (SNP) of the Note ninth intron of KIBRA gene, rs17070145, is No mutations of WWC1 are known. associated with human episodic memory performance (Papassotiropoulos et al., 2006). A Implicated in recent study using KIBRA-knockout mice showed that KIBRA is necessary for the contextual and Various cancers trace fear memory in adult mice (Makuch et al., Note 2011). KIBRA is also associated with Alzheimer's Genetic studies have identified Kibra as a tumor disease and recurrent depressive disorders suppressor in Drosophila. Kibra functions together (Corneveaux et al., 2008; Galecki et al., 2010). with Merlin and Expanded to regulate Hippo signaling pathway, which controls tissue growth References and organ size (Baumgartner et al., 2010; Genevet Kremerskothen J, Plaas C, Büther K, Finger I, Veltel S, et al., 2010; Yu et al., 2010). This function of Matanis T, Liedtke T, Barnekow A. Characterization of KIBRA is also conserved in mammals. Methylation KIBRA, a novel WW domain-containing protein. Biochem status of KIBRA is correlated with prognosis of Biophys Res Commun. 2003 Jan 24;300(4):862-7 chronic lymphocytic leukemia and specific genetic Büther K, Plaas C, Barnekow A, Kremerskothen J. KIBRA event in B-cell acute lymphocytic leukemia is a novel substrate for protein kinase Czeta. Biochem (Shinawi et al., 2012; Hill et al., 2011). Biophys Res Commun. 2004 May 7;317(3):703-7 Cell cycle Papassotiropoulos A, Stephan DA, Huentelman MJ, Hoerndli FJ, Craig DW, Pearson JV, Huynh KD, Brunner F, Note Corneveaux J, Osborne D, Wollmer MA, Aerni A, Coluccia KIBRA is regulated by cyclin-dependent kinase 1 D, Hänggi J, Mondadori CR, Buchmann A, Reiman EM, Caselli RJ, Henke K, de Quervain DJ. Common Kibra (CDK1) and cell division cycle 14A/B alleles are associated with human memory performance. phosphatases (CDC14) and thus regulates cell-cycle Science. 2006 Oct 20;314(5798):475-8 progression (Ji et al., 2012). Besides, KIBRA Rayala SK, den Hollander P, Manavathi B, Talukder AH, interacts and regulates mitotic kinase aurora during Song C, Peng S, Barnekow A, Kremerskothen J, Kumar R. mitosis and is required for precise mitotic spindle Essential role of KIBRA in co-activator function of dynein assembly and chromosome alignment (Xiao et al., light chain 1 in mammalian cells. J Biol Chem. 2006 Jul 2011; Zhang et al., 2012). 14;281(28):19092-9 Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4) 245 WWC1 (WW and C2 domain containing 1) Zhang L, Dong J Almeida OP, Schwab SG, Lautenschlager NT, Morar B, the Salvador/Warts/Hippo (SWH) tumor suppressor Greenop KR, Flicker L, Wildenauer D. KIBRA genetic network, is associated with specific genetic event in B-cell polymorphism influences episodic memory in later life, but acute lymphocytic leukemia. Epigenetics. 2011 does not increase the risk of mild cognitive impairment.
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