Point Mutations in the Tumor Suppressor Smad4/DPC4 Enhance Its Phosphorylation by GSK3 and Reversibly Inactivate TGF-β Signaling

Overview

Journal Mol Cell Oncol

Specialty Oncology

Date 2016 Jun 17

PMID 27308538

Citations 24

Authors

Hadrien Demagny

Edward M De Robertis

Affiliations

Soon will be listed here.

Abstract

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.

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