WWC1 (WW and C2 domain containing 1)

2013-08-01   Lin Zhang , Jixin Dong 

Eppley Institute for Research in Cancer, Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198-5950, USA

Identity

HGNC
LOCATION
5q34
LOCUSID
ALIAS
HBEBP3,HBEBP36,KIBRA,MEMRYQTL,PPP1R168
FUSION GENES

DNA/RNA

Atlas Image
Diagram of WWC1 DNA which contains 23 exons shown with blue boxes.

Description

The gene of WWC1 locates on chromosome 5q34, with 23 exons crossing 180244bp (including un-translated regions) on the plus strand. In total 137 single nucleotide polymorphisms are present in ≥ 1% of samples according to UCSC database.

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).

Pseudogene

No pseudogene of WWC1 is known.

Proteins

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
Atlas Image
Structure of human KIBRA. KIBRA contains two WW domains, a C2 domain, a glutamic acid-rich domain and a PDZ binding motif.

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 Alzheimers 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).
Atlas Image

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.

Mutations

Note

No mutations of WWC1 are known.

Implicated in

Entity name
Memory performance
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 Alzheimers disease and recurrent depressive disorders (Corneveaux et al., 2008; Galecki et al., 2010).
Entity name
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).
Entity name
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).
Entity name
Epithelial-mesenchymal transition
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).

Bibliography

Pubmed IDLast YearTitleAuthors
181944572008KIBRA genetic polymorphism influences episodic memory in later life, but does not increase the risk of mild cognitive impairment.Almeida OP et al
193979512009Association of KIBRA and memory.Bates TC et al
201596002010The WW domain protein Kibra acts upstream of Hippo in Drosophila.Baumgartner R et al
150813972004KIBRA is a novel substrate for protein kinase Czeta.Büther K et al
187898302010Evidence for an association between KIBRA and late-onset Alzheimer's disease.Corneveaux JJ et al
185961232008KIBRA modulates directional migration of podocytes.Duning K et al
201508792010Single nucleotide polymorphism of the KIBRA gene in recurrent depressive disorders.Galecki P et al
201595992010Kibra is a regulator of the Salvador/Warts/Hippo signaling network.Genevet A et al
211735722011Frequent 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 et al
227840932012Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression.Ji M et al
186720312008Temporal-spatial expression and novel biochemical properties of the memory-related protein KIBRA.Johannsen S et al
125599522003Characterization of KIBRA, a novel WW domain-containing protein.Kremerskothen J et al
219436002011Regulation of AMPA receptor function by the human memory-associated gene KIBRA.Makuch L et al
226140062013KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals.Moleirinho S et al
170531492006Common Kibra alleles are associated with human memory performance.Papassotiropoulos A et al
166847792006Essential role of KIBRA in co-activator function of dynein light chain 1 in mammalian cells.Rayala SK et al
173530702008KIBRA gene variants are associated with episodic memory in healthy elderly.Schaper K et al
224307962012KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia.Shinawi T et al
218786422011KIBRA protein phosphorylation is regulated by mitotic kinase aurora and protein phosphatase 1.Xiao L et al
231637442013High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis.Yoshihama Y et al
201595982010Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.Yu J et al
229043282012KIBRA regulates aurora kinase activity and is required for precise chromosome alignment during mitosis.Zhang L et al

Other Information

Locus ID:

NCBI: 23286
MIM: 610533
HGNC: 29435
Ensembl: ENSG00000113645

Variants:

dbSNP: 23286
ClinVar: 23286
TCGA: ENSG00000113645
COSMIC: WWC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000113645ENST00000265293Q8IX03
ENSG00000113645ENST00000393895H3BLZ3
ENSG00000113645ENST00000521089Q8IX03
ENSG00000113645ENST00000524038H0YAU4
ENSG00000113645ENST00000524228H0YBE8

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

PathwaySourceExternal ID
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Hippo signalingKEGGhsa_M00683
Hippo signalingKEGGM00683
Signal TransductionREACTOMER-HSA-162582
Signaling by HippoREACTOMER-HSA-2028269
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
170531492006Common Kibra alleles are associated with human memory performance.153
170531492006Common Kibra alleles are associated with human memory performance.153
212332122011KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.73
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
125599522003Characterization of KIBRA, a novel WW domain-containing protein.59
226140062013KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals.53
219436002011Regulation of AMPA receptor function by the human memory-associated gene KIBRA.49
173530702008KIBRA gene variants are associated with episodic memory in healthy elderly.47
173530702008KIBRA gene variants are associated with episodic memory in healthy elderly.47
187898302010Evidence for an association between KIBRA and late-onset Alzheimer's disease.43

Citation

Lin Zhang ; Jixin Dong

WWC1 (WW and C2 domain containing 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/45810/wwc1