Alternative titles; symbols
HGNC Approved Gene Symbol: WWC1
Cytogenetic location: 5q34 Genomic coordinates (GRCh38): 5:168,291,645-168,472,303 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q34 | [Memory, enhanced, QTL] | 615602 | 3 |
WWC1 is a scaffolding protein implicated in the regulation of cell proliferation and organ size through modulation of the Hippo signaling pathway (see 605030) (Qi et al., 2022).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned a partial WWC1 sequence, which they designated KIAA0869. RT-PCR ELISA detected highest expression in liver and kidney, intermediate expression in brain, lung, pancreas, and ovary, weak expression in heart and testis, and no expression in skeletal muscle and spleen.
Using dendrin (DDN; 610588) as bait in a yeast 2-hybrid screen of a brain cDNA library, followed by 5-prime RACE, Kremerskothen et al. (2003) cloned full-length WWC1, which they called KIBRA. The deduced 1,113-amino acid protein has a calculated molecular mass of about 125 kD. It contains 2 N-terminal WW domains, and a C2-like domain and glutamine-rich domain in its C-terminal half. Northern blot analysis detected a major 4.3-kb transcript predominantly expressed in kidney and brain. Following expression in green monkey kidney cells, Western blot analysis detected human KIBRA and endogenous Kibra at an apparent molecular mass of 125 kD. Fluorescence microscopy localized KIBRA predominantly to the cytoplasm, with perinuclear enrichment.
Rayala et al. (2006) identified a nuclear localization signal between KIBRA amino acids 361 and 376. Western blot analysis detected KIBRA in all subcellular fractions of fractionated breast cancer cells, including the chromatin fraction. In vivo labeling with orthophosphoric acid revealed that KIBRA is a phosphoprotein.
By quantitative RT-PCR, Papassotiropoulos et al. (2006) found expression of human KIBRA in memory-related brain structures including the hippocampus and the temporal lobe. In mice, in situ hybridization showed that KIBRA expression is highest in the dentate gyrus and the CA1 region of the hippocampal formation, 2 key regions for memory.
Wennmann et al. (2014) reported that the human WWC1 protein shares 49% and 40% amino acid identity with WWC2 (620110) and WWC3 (301089), respectively. Like all WWC proteins, WWC1 contains 2 N-terminal WW domains, an internal C2 domain, a binding site for atypical protein kinase C (aPKC; see 176982), and a C-terminal class III PDZ interaction motif (ADDV). WWC1 also contains phosphorylation motifs conserved in other WWC proteins. Unlike other WWC proteins, WWC1 has a glutamic acid-rich region adjacent to the C2 domain. RT-PCR analysis of rat tissues revealed that all 3 WWC genes were expressed at moderate levels in kidney, brain (cerebrum), and liver and at high levels in lung. In testis, WWC2 was predominantly expressed, whereas ovary had enhanced levels of WWC3.
By genomic sequence analysis, Kremerskothen et al. (2003) mapped the WWC1 gene to chromosome 5q34-q35.2.
Gross (2022) mapped the WWC1 gene to chromosome 5q34 based on an alignment of the WWC1 sequence (GenBank BC004394) with the genomic sequence (GRCh38).
By phage display analysis, Kremerskothen et al. (2003) showed that the first WW domain of KIBRA mediated its binding to proteins containing an RxPPxY sequence. By yeast 2-hybrid analysis of a human brain cDNA expression library, Buther et al. (2004) found that KIBRA interacted with the PKM-zeta form of PRKC-zeta (PRKCZ; 176982), which lacks regulatory domains, but not with full-length PRKCZ. Mutation analysis indicated that a 44-amino acid fragment of KIBRA that contains 4 potential PKC phosphorylation motifs interacted with the kinase domain of PRKCZ. Within this 44-amino acid fragment, PRKCZ phosphorylated KIBRA at serines 975 and 978. Buther et al. (2004) stated that this KIBRA fragment is also part of a dimerization domain.
Using a pull-down assay with human breast cancer cell lysates, Rayala et al. (2006) found that dynein light chain-1 (DLC1, DYNLL1; 601562) interacted with KIBRA. The KIBRA-DLC1 complex was recruited to estrogen receptor (see ESR1; 133430)-positive promoters and the interaction of KIBRA with DLC1 was mandatory for the recruitment and transactivation functions of ESR or DLC1 to the target chromatin. KIBRA also interacted with histone H3 (see 602810) via its glutamic acid-rich region. Rayala et al. (2006) concluded that the DLC1-KIBRA interaction is essential for ESR transactivation in breast cancer cells, and that the interaction of KIBRA with histone H3 may confer optimal ESR transactivation.
Using a yeast 2-hybrid system, Wennmann et al. (2014) showed that WWC1, WWC2, and WWC3 formed homo- and heterodimeric complexes. In line with their structural similarity, all 3 WWC proteins shared a common set of binding partners. Immunoprecipitation analysis revealed that WWC1 interacted with LATS1 (603473) and LATS2 (604861) in HEK293T cells. Interaction with WWC1 activated the LATS kinases to inhibit Hippo signaling, leading to reduced proliferation of HEK293T cells in vitro. This finding was confirmed in Drosophila in vivo, as expression of human WWC1 modulated the Hippo pathway to regulate organ size in Drosophila.
By ectopic expression and knockdown analyses in HEK293A cells, Qi et al. (2022) showed that all 3 human WWC proteins induced activation of LATS1 and LATS2 and increased their kinase activity. LATS1 and LATS2 were not directly activated by the WWC proteins, but were instead activated by MST1 (STK4; 142408) and MST2 (STK3; 605030), and their activation was dependent on SAV1 (607203). The WWC proteins mediated LATS activation by linking LATS1/LATS2 and SAV1. SAV1, in turn, brought in MST1/MST2 to form a 4-component signaling module to phosphorylate and activate LATS1/LATS2. Knockout analysis in mice revealed that concurrent deletion of both Sav1 and Wwc1/Wwc2 in liver largely phenocopied Mst1/Mst2 deficiency in terms of Hippo signaling, organ size, and tumorigenesis, supporting a critical function of the WWC proteins and Sav1 in mediating Lats1/Lats2 activation by Mst1/Mst2 by serving as adaptor molecules. The MST-SAV-WWC-LATS signaling module was conserved in Drosophila, suggesting an evolutionarily conserved role of SAV and WWC in transducing signals from MST to LATS. Deletion analysis identified an N-terminal portion of the human WWC proteins and the Drosophila ortholog, which the authors designated SuperHippo, that mimicked the full-length WWC proteins and robustly activated LATS1/LATS2 and inhibited YAP (YAP1; 606608)/TAZ (607392). By inhibiting YAP/TAZ activity, expression of SuperHippo effectively suppressed tumorigenesis both in vitro and in vivo.
In a genomewide screen to identify memory-related gene variants, Papassotiropoulos et al. (2006) identified a SNP (rs1707145; see 610533.0001) in intron 9 of the KIBRA gene that was significantly associated with memory performance (MEMRYQTL; 615602) in 3 independent, cognitively normal cohorts from Switzerland and the United States. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval.
Duning et al. (2013) identified 2 common missense SNPs, met734 to ile (M734I; rs3822660) and ser735 to ala (S735A; rs3822659) (see 610533.0001), in exon 15 of the KIBRA gene that were in complete linkage disequilibrium with SNP rs17070145 in intron 9. The 2 exonic SNPS are in the KIBRA C2 domain within a moderately conserved region preceding the alpha-helix of that domain. Duning et al. (2013) performed biochemical structural analyses and demonstrated that the KIBRA C2 domain has a bona fide lipid-binding capacity and a preference toward phosphatidylinositol 3-phosphate that is altered in the variant carrying I734 and A735 as well as a weaker interaction with PI(4P), PI(5P), and PI(4,5)P(2).
By phylogenetic analysis, Wennmann et al. (2014) showed that the WWC genes arose in the ancestor of bilateral animals (clades such as insects and vertebrates) from a single founder gene most similar to the present Kibra/Wwc1-like sequence of Drosophila. This situation was still maintained until the common ancestor of lancelet and vertebrates. In fish, a progenitor-like sequence of mammalian Kibra/Wwc1 and Wwc2 was expressed together with Wwc3. The 3 WWC family members, Wwc1, Wwc2, and Wwc3, were found in all tetrapods, except for a large genomic deletion including Wwc3 in mouse.
Papassotiropoulos et al. (2006) identified a common C-to-T substitution (rs17070145) within the ninth intron of the KIBRA gene that was associated with memory performance (MEMRYQTL; 615602). Carriers of the KIBRA rs17070145 T allele had a 24% better free recall performance 5 minutes after word presentation (p = 0.000004) and 19% better free recall performance 24 hours after word presentation (p = 0.0008) than did noncarriers.
Schaper et al. (2008) studied cognition in aging in 64 carefully phenotyped, cognitively healthy participants. All subjects were free of memory complaints and showed intact cognitive performance by scoring within 1.5 standard deviations of the German age-, gender-, and education-adjusted range on the CERAD neuropsychologic battery. None was suffering from any psychiatric, neurologic, or significant medical disorder and none was taking medication with known effect on cognition. Thirty-five participants were carriers of the rs17070145 CT (n = 33) or TT (n = 2) genotype (23 males, 12 females; mean age, 67.1 +/- 7.3; years of formal education, 15.1 +/- 3.1; verbal IQ, 123.7 +/- 11.9). CT and TT carriers were combined in parallel to the original study by Papassotiropoulos et al. (2006). Twenty-nine subjects were CC carriers (17 males, 12 females; mean age, 66.8 +/- 8.6; years of formal education, 14.1 +/- 2.8; verbal IQ, 122.4 +/- 10.9). Schaper et al. (2008) observed a statistically significant poorer performance in total recall and in recognition in CC genotype carriers compared with the CT/TT genotype group. Free recall after interference and delayed free recall showed a trend toward difference between both groups. There was no difference between groups in verbal fluency.
Palombo et al. (2013) investigated whether the KIBRA C-to-T polymorphism is associated with volume differences in the human hippocampus and whether specific subfields are differentially affected by KIBRA genotype. High-resolution MRI (T2-weighted, voxel size = 0.4 x 0.4 mm, in-plane) was used to manually segment hippocampal cornu ammonis (CA) subfields, dentate gyrus, and the subiculum as well as adjacent medial temporal lobe cortices in healthy carriers and noncarriers of the KIBRA T allele (rs17070145). Overall, Palombo et al. (2013) found that T carriers had a larger hippocampal volume relative to noncarriers. The structural differences observed were specific to the CA fields and dentate gyrus regions of the hippocampus, suggesting a potential neural mechanism for the effects of KIBRA on episodic memory performance reported previously.
Milnik et al. (2012) reported 2 random effects metaanalyses testing the association of rs17070145 with episodic and working memory. All currently available population-based association studies that investigated effects of rs17070145 on episodic or working memory were included in the analyses. Where performance measures for multiple domain-specific tasks were available for a given study population, averaged effect size estimates were calculated. The performed metaanalyses relied on 17 samples that were tested for episodic memory performance (n = 8,909) and 9 samples that had performed working memory tasks (n = 4,696). Milnik et al. (2012) reported a significant association of rs17070145 with both episodic (r = 0.068, p = 0.001) and working memory (r = 0.035, p = 0.018). Milnik et al. (2012) concluded that rs17070145 explains 0.5% of the variance for episodic memory tasks and 0.1% of the variance for working memory tasks in samples of primarily Caucasian background.
Duning et al. (2013) identified 2 common missense SNPS in exon 15 of the KIBRA gene, M734I (rs3822660), resulting from a G to T substitution, and S735A (rs3822659), resulting from a T to G substitution, that were in complete linkage disequilibrium with rs17070145 in intron 9. The 2 exonic SNPS are in the KIBRA C2 domain within a moderately conserved region preceding the alpha-helix of that domain. Duning et al. (2013) performed biochemical structural analyses and demonstrated that the KIBRA C2 domain has a bona fide lipid-binding capacity and a preference toward phosphatidylinositol 3-phosphate that is altered in the variant carrying I734 and A735 as well as a weaker interaction with PI(4P), PI(5P), and PI(4,5)P(2).
Buther, K., Plaas, C., Barnekow, A., Kremerskothen, J. KIBRA is a novel substrate for protein kinase C-zeta. Biochem. Biophys. Res. Commun. 317: 703-707, 2004. [PubMed: 15081397] [Full Text: https://doi.org/10.1016/j.bbrc.2004.03.107]
Duning, K., Wennmann, D. O., Bokemeyer, A., Reissner, C., Wershching, H., Thomas, C., Buschert, J., Guske, K., Franzke, V., Floel, A., Lohmann, H., Knecht, S., and 13 others. Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance. Transl. Psychiat. 3: e272, 2013. Note: Electronic Article. [PubMed: 23778582] [Full Text: https://doi.org/10.1038/tp.2013.49]
Gross, M. B. Personal Communication. Baltimore, Md. 10/28/2022.
Kremerskothen, J., Plaas, C., Buther, K., Finger, I., Veltel, S., Matanis, T., Liedtke, T., Barnekow, A. Characterization of KIBRA, a novel WW domain-containing protein. Biochem. Biophys. Res. Commun. 300: 862-867, 2003. [PubMed: 12559952] [Full Text: https://doi.org/10.1016/s0006-291x(02)02945-5]
Milnik, A., Heck, A., Vogler, C., Heinze, H.-J., de Quervain, D. J.-F., Papassotiropoulos, A. Association of KIBRA with episodic and working memory: a meta-analysis. Am. J. Med. Genet. 159B: 958-969, 2012. [PubMed: 23065961] [Full Text: https://doi.org/10.1002/ajmg.b.32101]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Oharo, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Palombo, D. J., Amaral, R. S. C., Olsen, R. K., Muller, D. J., Todd, R. M., Anderson, A. K., Levine, B. KIBRA polymorphism is associated with individual differences in hippocampal subregions: evidence from anatomical segmentation using high-resolution MRI. J. Neurosci. 33: 13088-13093, 2013. [PubMed: 23926262] [Full Text: https://doi.org/10.1523/JNEUROSCI.1406-13.2013]
Papassotiropoulos, A., Stephan, D. A., Huentelman, M. J., Hoerndli, F. J., Craig, D. W., Pearson, J. V., Huynh, K.-D., Brunner, F., Corneveaux, J., Osborne, D., Wollmer, M. A., Aerni, A., Coluccia, D., Hanggi, J., Mondadori, C. R. A., Buchmann, A., Reiman, E. M., Caselli, R. J., Henke, K., de Quervain, D. J.-F. Common Kibra alleles are associated with human memory performance. Science 314: 475-478, 2006. [PubMed: 17053149] [Full Text: https://doi.org/10.1126/science.1129837]
Qi, S., Zhu, Y., Liu, X., Li, P., Wang, Y., Zeng, Y., Yu, A., Wang, Y., Sha, Z., Zhong, Z., Zhu, R., Yuan, H., Ye, D., Huang, S., Ling, C., Xu, Y., Zhou, D., Zhang, L., Yu, F. X. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy. Molec. Cell 82: 1850-1864, 2022. [PubMed: 35429439] [Full Text: https://doi.org/10.1016/j.molcel.2022.03.027]
Rayala, S. K., den Hollander, P., Manavathi, B., Talukder, A. H., 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. 281: 19092-19099, 2006. [PubMed: 16684779] [Full Text: https://doi.org/10.1074/jbc.M600021200]
Schaper, K., Kolsch, H., Popp, J., Wagner, M., Jessen, F. KIBRA gene variants are associated with episodic memory in healthy elderly. Neurobiol. Aging 29: 1123-1125, 2008. [PubMed: 17353070] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2007.02.001]
Wennmann, D. O., Schmitz, J., Wehr, M. C., Krahn, M. P., Koschmal, N., Gromnitza, S., Schulze, U., Weide, T., Chekuri, A., Skryabin, B. V., Gerke, V., Pavenstadt, H., Duning, K., Kremerskothen, J. Evolutionary and molecular facts link the WWC protein family to Hippo signaling. Molec. Biol. Evol. 31: 1710-1723, 2014. [PubMed: 24682284] [Full Text: https://doi.org/10.1093/molbev/msu115]