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Published online 12 January 2004. doi:10.1083/jcb.200307151
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 2, 291-300
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Article

 GADD34–PP1c recruited by Smad7 dephosphorylates TGFß type I receptor

Weibin Shi1, Chuanxi Sun1, Bin He2, Wencheng Xiong1, Xingming Shi1, Dachun Yao1, and Xu Cao1

1 Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294
2 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612

Address correspondence to Xu Cao, 1670 University Blvd., VH G002, Birmingham, AL 35294-0019. Tel.: (205) 934-0162. Fax: (205) 934-1775. email: cao{at}path.uab.edu

The cascade of phosphorylation is a pivotal event in transforming growth factor ß (TGFß) signaling. Reversible phosphorylation regulates fundamental aspects of cell activity. TGFß-induced Smad7 binds to type I receptor (TGFß type I receptor; TßRI) functioning as a receptor kinase antagonist. We found Smad7 interacts with growth arrest and DNA damage protein, GADD34, a regulatory subunit of the protein phosphatase 1 (PP1) holoenzyme, which subsequently recruits catalytic subunit of PP1 (PP1c) to dephosphorylate TßRI. Blocking Smad7 expression by RNA interference inhibits association of GADD34–PP1c complex with TßRI, indicating Smad7 acts as an adaptor protein in the formation of the PP1 holoenzyme that targets TßRI for dephosphorylation. SARA (Smad anchor for receptor activation) enhances the recruitment PP1c to the Smad7–GADD34 complex by controlling the specific subcellular localization of PP1c. Importantly, GADD34–PP1c recruited by Smad7 inhibits TGFß-induced cell cycle arrest and mediates TGFß resistance in responding to UV light irradiation. The dephosphorylation of TßRI mediated by Smad7 is an effective mechanism for governing negative feedback in TGFß signaling.

Key Words: TGFß; Smad7; GADD34; phosphatase; SARA

The online version of this article contains supplemental material.

Abbreviations used in this paper: GADD, growth arrest and DNA damage; I-1, inhibitor 1; OA, okadaic acid; PP1, protein phosphatase 1; PP1c, catalytic subunit of protein phosphatase 1; PTP, protein tyrosine phosphatase; RNAi, RNA interference; R-Smads, receptor-regulated Smads; SARA, Smad anchor for receptor activation; siRNA, small interfering RNA; TßRI, transforming growth factor ß type I receptor.


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