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 |
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| Structure of human KIBRA. KIBRA contains two WW domains, a C2 domain, a glutamic acid-rich domain and a PDZ binding motif. |
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Description | 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). 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). |
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. 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). |
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Homology | 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. |
KIBRA genetic polymorphism influences episodic memory in later life, but does not increase the risk of mild cognitive impairment. |
Almeida OP, Schwab SG, Lautenschlager NT, Morar B, Greenop KR, Flicker L, Wildenauer D. |
J Cell Mol Med. 2008 Sep-Oct;12(5A):1672-6. doi: 10.1111/j.1582-4934.2008.00229.x. Epub 2008 Jan 11. |
PMID 18194457 |
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Association of KIBRA and memory. |
Bates TC, Price JF, Harris SE, Marioni RE, Fowkes FG, Stewart MC, Murray GD, Whalley LJ, Starr JM, Deary IJ. |
Neurosci Lett. 2009 Jul 24;458(3):140-3. doi: 10.1016/j.neulet.2009.04.050. Epub 2009 May 3. |
PMID 19397951 |
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The WW domain protein Kibra acts upstream of Hippo in Drosophila. |
Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H. |
Dev Cell. 2010 Feb 16;18(2):309-16. doi: 10.1016/j.devcel.2009.12.013. |
PMID 20159600 |
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KIBRA is a novel substrate for protein kinase Czeta. |
Buther K, Plaas C, Barnekow A, Kremerskothen J. |
Biochem Biophys Res Commun. 2004 May 7;317(3):703-7. |
PMID 15081397 |
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Evidence for an association between KIBRA and late-onset Alzheimer's disease. |
Corneveaux JJ, Liang WS, Reiman EM, Webster JA, Myers AJ, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince 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, Kolsch H, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Papassotiropoulos A, Stephan DA, Huentelman MJ. |
Neurobiol Aging. 2010 Jun;31(6):901-9. doi: 10.1016/j.neurobiolaging.2008.07.014. Epub 2008 Sep 13. |
PMID 18789830 |
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KIBRA modulates directional migration of podocytes. |
Duning K, Schurek EM, Schluter M, Bayer M, Reinhardt HC, Schwab A, Schaefer L, Benzing T, Schermer B, Saleem MA, Huber TB, Bachmann S, Kremerskothen J, Weide T, Pavenstadt H. |
J Am Soc Nephrol. 2008 Oct;19(10):1891-903. doi: 10.1681/ASN.2007080916. Epub 2008 Jul 2. |
PMID 18596123 |
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Single nucleotide polymorphism of the KIBRA gene in recurrent depressive disorders. |
Galecki P, Szemraj J, Florkowski A, Talarowska M, Bienkiewicz M, Galecka E, Lewinski A. |
Neuro Endocrinol Lett. 2010;31(1):97-102. |
PMID 20150879 |
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Kibra is a regulator of the Salvador/Warts/Hippo signaling network. |
Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N. |
Dev Cell. 2010 Feb 16;18(2):300-8. doi: 10.1016/j.devcel.2009.12.011. |
PMID 20159599 |
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Frequent epigenetic inactivation of KIBRA, an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia. |
Hill VK, Dunwell TL, Catchpoole D, Krex D, Brini AT, Griffiths M, Craddock C, Maher ER, Latif F. |
Epigenetics. 2011 Mar;6(3):326-32. Epub 2011 Mar 1. |
PMID 21173572 |
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Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression. |
Ji M, Yang S, Chen Y, Xiao L, Zhang L, Dong J. |
Biochem J. 2012 Oct 1;447(1):93-102. doi: 10.1042/BJ20120751. |
PMID 22784093 |
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Temporal-spatial expression and novel biochemical properties of the memory-related protein KIBRA. |
Johannsen S, Duning K, Pavenstadt H, Kremerskothen J, Boeckers TM. |
Neuroscience. 2008 Sep 9;155(4):1165-73. doi: 10.1016/j.neuroscience.2008.06.054. Epub 2008 Jul 3. |
PMID 18672031 |
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Characterization of KIBRA, a novel WW domain-containing protein. |
Kremerskothen J, Plaas C, Buther K, Finger I, Veltel S, Matanis T, Liedtke T, Barnekow A. |
Biochem Biophys Res Commun. 2003 Jan 24;300(4):862-7. |
PMID 12559952 |
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Regulation of AMPA receptor function by the human memory-associated gene KIBRA. |
Makuch L, Volk L, Anggono V, Johnson RC, Yu Y, Duning K, Kremerskothen J, Xia J, Takamiya K, Huganir RL. |
Neuron. 2011 Sep 22;71(6):1022-9. doi: 10.1016/j.neuron.2011.08.017. Epub 2011 Sep 21. |
PMID 21943600 |
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KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals. |
Moleirinho S, Chang N, Sims AH, Tilston-Lunel AM, Angus L, Steele A, Boswell V, Barnett SC, Ormandy C, Faratian D, Gunn-Moore FJ, Reynolds PA. |
Oncogene. 2013 Apr 4;32(14):1821-30. doi: 10.1038/onc.2012.196. Epub 2012 May 21. |
PMID 22614006 |
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Common Kibra alleles are associated with human memory performance. |
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, Hanggi J, Mondadori CR, Buchmann A, Reiman EM, Caselli RJ, Henke K, de Quervain DJ. |
Science. 2006 Oct 20;314(5798):475-8. |
PMID 17053149 |
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Essential role of KIBRA in co-activator function of dynein light chain 1 in mammalian cells. |
Rayala SK, den Hollander P, Manavathi B, Talukder AH, Song C, Peng S, Barnekow A, Kremerskothen J, Kumar R. |
J Biol Chem. 2006 Jul 14;281(28):19092-9. Epub 2006 May 9. |
PMID 16684779 |
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KIBRA gene variants are associated with episodic memory in healthy elderly. |
Schaper K, Kolsch H, Popp J, Wagner M, Jessen F. |
Neurobiol Aging. 2008 Jul;29(7):1123-5. Epub 2007 Mar 13. |
PMID 17353070 |
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KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia. |
Shinawi T, Hill V, Dagklis A, Baliakas P, Stamatopoulos K, Agathanggelou A, Stankovic T, Maher ER, Ghia P, Latif F. |
Epigenetics. 2012 Mar;7(3):211-5. doi: 10.4161/epi.7.3.19222. |
PMID 22430796 |
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KIBRA protein phosphorylation is regulated by mitotic kinase aurora and protein phosphatase 1. |
Xiao L, Chen Y, Ji M, Volle DJ, Lewis RE, Tsai MY, Dong J. |
J Biol Chem. 2011b Oct 21;286(42):36304-15. doi: 10.1074/jbc.M111.246850. Epub 2011 Aug 30. |
PMID 21878642 |
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High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis. |
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. |
Cancer Sci. 2013 Feb;104(2):259-65. doi: 10.1111/cas.12066. Epub 2012 Dec 27. |
PMID 23163744 |
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Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. |
Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. |
Dev Cell. 2010 Feb 16;18(2):288-99. doi: 10.1016/j.devcel.2009.12.012. |
PMID 20159598 |
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KIBRA regulates aurora kinase activity and is required for precise chromosome alignment during mitosis. |
Zhang L, Iyer J, Chowdhury A, Ji M, Xiao L, Yang S, Chen Y, Tsai MY, Dong J. |
J Biol Chem. 2012 Oct 5;287(41):34069-77. doi: 10.1074/jbc.M112.385518. Epub 2012 Aug 17. |
PMID 22904328 |
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