Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling.
The tumor suppressor Smad4/DPC4 is an essential transcription factor in the TGF-β pathway and is frequently mutated or deleted in prostate, colorectal, and pancreatic carcinomas. We recently discovered that Smad4 activity and stability are regulated by the FGF/EGF and Wnt signaling pathways through a series of MAPK and GSK3 phosphorylation sites located in its linker region. In the present study, we report that loss-of-function associated with 2 point mutations commonly found in colorectal and pancreatic cancers results from enhanced Smad4 phosphorylation by GSK3, generating a phosphodegron that leads to subsequent β-TrCP-mediated polyubiquitination and proteasomal degradation. Using chemical GSK3 inhibitors, we show that Smad4 point mutant proteins can be stabilized and TGF-β signaling restored in cancer cells harboring such mutations.
Howard Hughes Medical Institute and Department of Biological Chemistry; University of California ; Los Angeles, CA USA.
Hadrien
H
Demagny
Howard Hughes Medical Institute and Department of Biological Chemistry; University of California ; Los Angeles, CA USA.
Edward M
EM
De Robertis
BMP; CDK; Caco-2; DPC4; GSK3; MAPK; Wnt/STOP; pancreatic cancer; prostate cancer; β-TrCP