Thursday, March 14, 2013
WNT signaling in cancer. A
Boston-based team and a Genentech Inc.-led team
have each identified a new kinase-v-yes-1 Yamaguchi sarcoma viral oncogene
homolog 1 (YES1;
kinase 4 (RIPK4;
respectively-that acts in wingless-type MMTV integration site (WNT)-driven
The Genentech team found that RIPK4 acts at the WNT
receptor complex to phosphorylate dishevelled dsh homolog 2 (DVL2). This induces b-catenin (CTNNB1) accumulation
in the cytoplasm (I[a]) and translocation to the nucleus to regulate
gene expression via the TCF family of transcription factors (I[b]).
RIPK4 also appears to play a role in cancer cells (II[a]), as the kinase
is overexpressed in ovarian cancers, and knocking down RIPK4 in a cancer cell
line decreased tumor growth in mice.
The Boston team found that in cancer cell lines with
increased b-catenin activity, b-catenin forms a
transcriptional complex with yes-associated protein 1
(YAP1) and YES1 that
regulates the increased expression of antiapoptotic genes (II[b]).
Knocking down YES1 decreased the formation of WNT-driven colon tumors in mice.