CTNNB1 is the gene which encodes the
ß-catenin protein. ß-catenin
is part of a complex of proteins that form
adherens junctions, which are important for the establishment and maintenance of epithelial
cell layers by regulating cell growth and adhesion between adjacent cells (Hartsock and
Nelson 2008). ß-catenin is also part of the canonical Wnt signaling
pathway (Figure 1). In the absence of Wnt signaling, glycogen synthase kinase-3 (GSK-3)
phosphorylates ß-catenin, thereby targeting ß-catenin for degradation via the
ubiquitin-proteasome system. When Wnt binds to its receptor, Frizzled, ß-catenin
phosphorylation and ubiquitin-mediated degradation are blocked. ß-catenin is then free
to translocate to the cell nucleus where it acts as a co-factor for the T-cell
factor/lymphoid enhancing factor (TCF/LEF) transcription factors. The ß-catenin-TCF/LEF
complex results in the activation of targets including c-MYC and Cyclin-D1 (for review, see
Giles, van Es, and
Mutant CTNNB1 (ß-catenin) has been implicated in the pathogenesis of several cancers
including melanoma, colorectal cancer, hepatocelluar carcinoma, and ovarian cancer (Giles, van Es,
and Clevers 2003).
Figure 1. Simplified schematic of the
Wnt signaling pathway. In the absence of
Wnt signaling, ß-catenin is phosphorylated by GSK-3, thereby resulting in
poly-ubiquitination and degradation by the 20S proteasome system. When Wnt binds to its
receptor, Frizzled, ß-catenin is
stabilized. ß-catenin subsequently translocates to the nucleus, where it acts as a
co-factor for the TCF/LEF family of transcription
Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. CTNNB1. My Cancer
(Updated December 4).
Last Updated: December 4, 2015
CTNNB1 (beta-catenin) in Melanoma
Somatic mutations in CTNNB1 have been
found in 2–4% of malignant melanomas in most series (COSMIC; Demunter et al. 2002; Omholt et al.
2001; Pollock and
Hayward 2002; Reifenberger
et al. 2002; Rimm
et al. 1999). One study reported a frequency of as high as 23% in melanoma cell lines
(Rubinfeld et al. 1997).
CTNNB1 mutations are rare in uveal melanoma (Edmunds et al.
2002). Whether the presence of CTNNB1 mutation correlates with sun exposure
remains to be determined.
The most common CTNNB1 (ß-catenin) mutations
detected in melanoma are missense mutations
which introduce amino acid substitutions at
either serine 37 or serine 45, both of which are putative glycogen synthase kinase 3ß (GSK3ß) phosphorylation sites. The result of these mutations is stabilization of the ß-
catenin protein and increased transcription of TCF/LEF-responsive target
genes (Rubinfeld et al.
1997; Worm et al.
Preclinical models have demonstrated that concurrent mutations
in ß-catenin and NRAS are synergistic in promoting melanoma formation (Delmas et al.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. CTNNB1 (beta-catenin) in
Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/ctnnb1/
(Updated June 18).
Last Updated: June 18, 2015
CTNNB1 (beta-catenin) c.110C>A (S37Y) Mutation in Melanoma
The S37Y mutation results in an amino acid substitution at position 37 in
ß-catenin, from a serine (S) to a tyrosine (Y). Serine 37 is a putative glycogen synthase
kinase 3ß (GSK3ß) phosphorylation site within ß-
catenin. The result of this mutation is
stabilization of the ß-catenin protein
and increased transcription of
TCF/LEF-responsive target genes (Rubinfeld et al.
1997; Worm et al.
2004). CTNNB1 (ß-catenin) mutations are usually found in tumors wild type for
NRAS, BRAF, KIT, and other driver mutations. Currently, there are no direct anti-ß-catenin
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. CTNNB1 (beta-catenin)
c.110C>A (S37Y) Mutation in Melanoma. My
Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/ctnnb1/105/
(Updated June 16).
Last Updated: June 16, 2015
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