TACE-Mediated Ectodomain Shedding of the Type I TGF-β Receptor Downregulates TGF-β Signaling

被引：108

作者：

Liu, Cheng ^{[1
,2
]}

Xu, Pinglong ^{[1
,2
]}

Lamouille, Samy ^{[1
,2
]}

Xu, Jian ^{[1
,2
]}

Derynck, Rik ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Cell Biol Program, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Program Dev Biol, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

来源：

MOLECULAR CELL | 2009年 / 35卷 / 01期

关键词：

ALPHA-CONVERTING-ENZYME; EPITHELIAL-CELL PLASTICITY; ERK MAP KINASE; INDEPENDENT PATHWAYS; CANCER; ACTIVATION; EXPRESSION; SMAD4; PHOSPHORYLATION; PROLIFERATION;

D O I：

10.1016/j.molcel.2009.06.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Regulating TGF-beta receptor presentation provides an avenue to alter a cell's responsiveness to TGF-beta. We report that activation of the Erk MAP kinase pathway decreases the TGF-beta-induced Smad3 activation due to decreased cell surface levels of the type I receptor T beta RI, but not the type II receptor. Inhibition of TACE activity or expression enhanced the cell surface T beta RI levels and TGF-beta-induced Smad3 and Akt activation. Accordingly, silencing TACE expression in cancer cells enhanced the T beta RI presentation and TGF-beta responsiveness, including the anti proliferative effect of TGF-beta, and epithelial-to-mesenchymal transition. These results establish a mechanism for downregulating TGF-beta signaling through TACE activation by the Erk MAP kinase pathway and a strategy for evasion of tumor suppression and modulation of epithelial-to-mesenchymal transition during cancer progression. The decreased growth inhibition by TGF-beta, due to elevated TACE activity, complements the growth stimulation resulting from increased release of TGF-alpha family ligands.

引用

页码：26 / 36

页数：11

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