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Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl.


ABSTRACT: Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration, and tumorigenesis. For the maintenance of homeostasis, EGF signaling should be tightly regulated to prevent the aberrant activation. Smad7 has been known as inhibitory Smad that blocks the signal transduction of transforming growth factor ?. In the process of cell proliferation or transformation, Smad7 has been shown the opposite activities as a promoter or suppressor depending on cell types or microenvironments. We found that the overexpression of Smad7 in human HaCaT keratinocyte cells and mouse skin tissues elevated EGF receptor (EGFR) activity by impairing ligand-induced ubiquitination and degradation of activated receptor, which is induced by the E3 ubiquitin ligase c-Cbl. The C-terminal MH2 region but not MH1 region of Smad7 is critical for interaction with c-Cbl to inhibit the ubiquitination of EGFR. Interestingly, wild-type Smad7, but not Smad6 or mutant Smad7, destabilized the EGF-induced complex formation of c-Cbl and EGFR. These data suggest a novel role for Smad7 as a promoter for prolonging the EGFR signal in keratinocyte and skin tissue by reducing its ligand-induced ubiquitination and degradation.

SUBMITTER: Ha Thi HT 

PROVIDER: S-EPMC4508311 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl.

Ha Thi Huyen Trang HT   Kim Hye-Youn HY   Choi Seo-Won SW   Kang Jin-Muk JM   Kim Seong-Jin SJ   Hong Suntaek S  

Molecular and cellular biology 20150608 16


Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration, and tumorigenesis. For the maintenance of homeostasis, EGF signaling should be tightly regulated to prevent the aberrant activation. Smad7 has been known as inhibitory Smad that blocks the signal transduction of transforming growth factor β. In the process of cell proliferation or transformation, Smad7 has been shown the opposite activities as a promoter or suppressor depending o  ...[more]

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