Beta-catenin

Beta-catenin (or β-catenin) is a protein that in humans is encoded by the CTNNB1 gene.^[1] In Drosophila, the homologous protein is called armadillo. β-catenin is a subunit of the cadherin protein complex and has been implicated as an integral component in the Wnt signaling pathway.

Structure

When β-catenin was sequenced, it was found to be a member of the armadillo family of proteins. These proteins have multiple copies of the so-called armadillo repeat domain, which is specialized for protein-protein binding. When β-catenin is not associated with cadherins and alpha-catenin, it can interact with other proteins such as ICAT and APC.

Function

β-Catenin is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. β-Catenin also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete.^[2]

Recent evidence suggests that β-catenin plays an important role in various aspects of liver biology including liver development (both embryonic and postnatal), liver regeneration following partial hepatectomy, HGF-induced hepatomegaly, liver zonation, and pathogenesis of liver cancer.^[3]

Role in the Wnt signaling pathway

When Wnt is not present, GSK-3 (a kinase) constitutively phosphorylates the β-catenin protein. β-catenin is associated with axin (scaffolding protein) complexed with GSK3 and APC (adenomatosis polyposis coli). The creation of said complex acts to substantially increase the phosphorylation of β-catenin by facilitating the action of GSK3. When β-catenin is phosphorylated, it is degraded and, thus, will not build up in the cell to a significant level. When Wnt binds to frizzled (Fz), its receptor, dishevelled (Dsh), is recruited to the membrane. GSK3 is inhibited by the activation of Dsh by Fz. Because of this, β-catenin is permitted to build up in the cytosol and can be subsequently translocated into the nucleus to perform a variety of functions. It can act in conjunction with TCF and LEF to activate specific target genes involved in different processes.

Clinical significance

The gene that codes for β-catenin can function as an oncogene.^[4] An increase in β-catenin production has been noted in those people with basal cell carcinoma and leads to the increase in proliferation of related tumors.^[5] Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Also, β-catenin binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon.

Interactions with other proteins

β-catenin contains armadillo repeats and is able to bind to other proteins. Inside cells, β-catenin can be found in complexes with cadherins, transcription factors (TF in Figure 2), and other proteins such as axin, a component of the Wnt signalling pathway and galectin-3, beta-galactoside-binding protein. The ability of β-catenin to bind to other proteins is regulated by tyrosine kinases^[6] and serine kinases such as GSK-3.^[7]

When β-catenin is not assembled in complexes with cadherins, it can form a complex with axin. While bound to axin, β-catenin can be phosphorylated by GSK-3, which creates a signal for the rapid ubiquitin-dependent degradation of β-catenin by proteosomes. Various signals such as the Wnt signalling pathway can inhibit GSK-3-mediated phosphorylation of β-catenin,^[8] allowing β-catenin to go to the cell nucleus, interact with transcription factors, and regulate gene transcription.

β-Catenin can be phosphorylated by other kinases such as protein kinase A (PKA). Phosphorylation of β-catenin by PKA has been associated with reduced degradation of β-catenin, increased levels of β-catenin in the nucleus and interaction of β-catenin with TCF family transcription factors to regulate gene expression.^[9]

In addition, β-catenin has been shown to interact with:

• Androgen receptor^{[10][11][12][13][14][15]}
• APC^{[16][17][18][19][20][21][22][23]}
• AXIN1^[24][25]
• CBY1^[26]
• CDH1,^{[17][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]}
• CDH2,^[49][50]
• CDH3^[47][51]
• CDK5R1^[52]
• CHUK,^[53]
• CTNNA1,^{[28][37][54][55][56]}
• CTNND1^[17][32]
• EGFR^[32][41][57]
• FHL2^[58]
• GSK3B^[19][59]
• HER2/neu^[33][57][60]
• HNF4A^[14]
• IKK2^[53]
• LEF1^{[61][62][63][64]}
• MAGI1^[42]
• MUC1^{[34][65][66][67][68][69][70]}
• NR5A1^[71][72]
• PCAF,^[73]
• PHF17^[74]
• Plakoglobin^[17][32]
• PTPN14^[75]
• PTPRF^[33][76]
• PTPRK^[77]
• PSEN1^[78][79][80]
• RuvB-like 1^[81]
• SMAD7^[61]
• SLC9A3R1,^[36]
• SMARCA4^[82]
• USP9X^[83]
• VE-cadherin^[84][85]
• PTK7^[86]

See also

• Catenin

References

Further reading

External links

• MeSH beta+Catenin
• "A diverse set of proteins modulate the canonical Wnt/β-catenin signaling pathway." at cancer.gov
• "The role of β-catenin in signal transduction, cell fate determination and trans-differentiation" at nih.gov
• "Researchers Offer First Direct Proof of How Arthritis Destroys Cartilage" at rochester.edu

This article incorporates text from the United States National Library of Medicine, which is in the public domain.