The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling

被引：67

作者：

Demagny, Hadrien ^{[1
,2
]}

Araki, Tatsuya ^{[1
,2
]}

De Robertis, Edward M. ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA

来源：

CELL REPORTS | 2014年 / 9卷 / 02期

关键词：

GROWTH-FACTOR-BETA; PROTEIN STABILITY; TRANSCRIPTIONAL ACTIVATION; MESODERM INDUCTION; NEURAL INDUCTION; CELL-GROWTH; BMP; PATHWAYS; CATENIN; TARGETS;

D O I：

10.1016/j.celrep.2014.09.020

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Smad4 is a major tumor suppressor currently thought to function constitutively in the transforming growth factor beta (TGF-beta)-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 beta-TrCP. In the presence of FGF, Wnt potentiates TGF-beta 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-beta 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.

引用

页码：688 / 700

页数：13

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