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Cell Rep. 2014 Oct 23;9(2):688-700. doi: 10.1016/j.celrep.2014.09.020. Epub 2014 Oct 16.

The tumor suppressor Smad4/DPC4 is regulated by phosphorylations that integrate FGF, Wnt, and TGF-β signaling.

Author information

1
Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA.
2
Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095-1662, USA. Electronic address: ederobertis@mednet.ucla.edu.

Abstract

Smad4 is a major tumor suppressor currently thought to function constitutively in the transforming growth factor β (TGF-β)-signaling pathway. Here, we report that Smad4 activity is directly regulated by the Wnt and fibroblast growth factor (FGF) pathways through GSK3 and mitogen-activated protein kinase (MAPK) phosphorylation sites. FGF activates MAPK, which primes three sequential GSK3 phosphorylations that generate a Wnt-regulated phosphodegron bound by the ubiquitin E3 ligase β-TrCP. In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. When MAPK is not activated, the Wnt and TGF-β signaling pathways remain insulated from each other. In Xenopus embryos, these Smad4 phosphorylations regulate germ-layer specification and Spemann organizer formation. The results show that three major signaling pathways critical in development and cancer are integrated at the level of Smad4.

PMID:
25373906
DOI:
10.1016/j.celrep.2014.09.020
[Indexed for MEDLINE]
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