Beta-catenin


Beta-catenin

Beta-catenin is a subunit of the cadherin protein complex. In "Drosophila", the homologous protein is called "armadillo". Beta-catenin has been implicated as an integral component in the Wnt signaling pathway.

It can function as an oncogene.cite journal |author=Wang X, Goode EL, Fredericksen ZS, "et al" |title=Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer |journal=Cancer Epidemiol. Biomarkers Prev. |volume=17 |issue=8 |pages=2101–8 |year=2008 |month=August |pmid=18708403 |doi=10.1158/1055-9965.EPI-08-0134 |url=http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18708403]

Function

When beta-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. An increase in beta-catenin production has been noted in those people who have Basal Cell Carcinoma and leads to the increase in proliferation of related tumors. [G. Saldanha, V. Ghura, L. Potter and A. Fletcher. "Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation" in "The British Journal of Dermatology" (2004) Volume 151, pages 157-164. Entrez Pubmed|15270885] When beta-catenin is not associated with cadherins and alpha-catenin, it can interact with other proteins such as ICAT and APC.

Role in liver biology

Recent evidence suggests that beta-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 hepatpomegaly, liver zonation, and pathogenesis of liver cancer. [cite journal |author=Thompson MD, Monga SP |title=WNT/beta-catenin signaling in liver health and disease |journal=Hepatology |volume=45 |issue=5 |pages=1298–305 |year=2007 |pmid=17464972 |doi=10.1002/hep.21651]

Interactions of beta-catenin with other proteins

As mentioned above, beta-catenin contains armadillo repeats and is able to bind to other proteins. Inside cells, beta-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. The ability of beta-catenin to bind to other proteins is regulated by tyrosine kinases [J. Lilien and J. Balsamo "The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin" in "Current opinion in cell biology" (2005) Volume 17, pages 459-465. Entrez Pubmed|16099633] and serine kinases such as GSK-3. [M. D. Castellone, H. Teramoto, B. O. Williams, K. M. Druey, J. S. Gutkind. "Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis" in "Science (2005) Volume 310, pages 1504-1510. Entrez Pubmed|16293724]

When beta-catenin is not assembled in complexes with cadherins, it can form a complex with axin. While bound to axin, beta-catenin can be phosphorylated by GSK-3, which creates a signal for the rapid ubiquitin-dependent degradation of beta-catenin by proteosomes. Various signals such as the Wnt signalling pathway can inhibit GSK-3-mediated phosphorylation of beta-catenin, [X. Liu, J. S. Rubin and A. R. Kimmel. "Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins" in "Current Biology" (2005) Volume 15, pages 1989-1997. Entrez Pubmed|16303557] allowing beta-catenin to go to the cell nucleus, interact with transcription factors, and regulate gene transcription.

Beta-catenin can be phosphorylated by other kinases such as protein kinase A (PKA). Phosphorylation of beta-catenin by PKA has been associated with reduced degradation of beta-catenin, increased levels of beta-catenin in the nucleus and interaction of beta-catenin with TCF family transcription factors to regulate gene expression. [S. Hino, C. Tanji, K. I. Nakayama and A. Kikuchi "Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination" in "Molecular and Cellular Biology" (2005) Volume 20, pages 9063-9072. Entrez Pubmed|16199882]

Role of beta-catenin in the Wnt signaling pathway

When Wnt is not present, GSK3 (a kinase) constitutively phosphorylates the beta-catenin protein. Beta-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 beta-catenin by facilitating the action of GSK3. When beta-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, beta-catenin is permited 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 to activate specific genes as well as cause the export of TCF from the nucleus.

ee also

*Catenin

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Kikuchi A |title=Regulation of beta-catenin signaling in the Wnt pathway. |journal=Biochem. Biophys. Res. Commun. |volume=268 |issue= 2 |pages= 243–8 |year= 2000 |pmid= 10679188 |doi= 10.1006/bbrc.1999.1860
*cite journal | author=Wilson PD |title=Polycystin: new aspects of structure, function, and regulation. |journal=J. Am. Soc. Nephrol. |volume=12 |issue= 4 |pages= 834–45 |year= 2001 |pmid= 11274246 |doi=
*cite journal | author=Kalluri R, Neilson EG |title=Epithelial-mesenchymal transition and its implications for fibrosis. |journal=J. Clin. Invest. |volume=112 |issue= 12 |pages= 1776–84 |year= 2004 |pmid= 14679171 |doi= 10.1172/JCI200320530
*cite journal | author=De Ferrari GV, Moon RT |title=The ups and downs of Wnt signaling in prevalent neurological disorders. |journal=Oncogene |volume=25 |issue= 57 |pages= 7545–53 |year= 2007 |pmid= 17143299 |doi= 10.1038/sj.onc.1210064

External links

*
* [http://ccr.cancer.gov/Staff/gallery.asp?profileid=5411 "A diverse set of proteins modulate the canonical Wnt/beta-catenin signaling pathway." at cancer.gov]
* [http://mammary.nih.gov/lgp/lab/slides/LGP-research-past.html#a1 "The role of beta-catenin in signal transduction, cell fate determination and trans-differentiation" at nih.gov]
* [http://www.urmc.rochester.edu/pr/news/story.cfm?id=2091 "Researchers Offer First Direct Proof of How Arthritis Destroys Cartilage" at rochester.edu]

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