The cascade of phosphorylation is a pivotal event in transforming growth factor β (TGFβ) signaling. Reversible phosphorylation regulates fundamental aspects of cell activity. TGFβ-induced Smad7 binds to type I receptor (TGFβ type I receptor; TβRI) 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 TβRI. Blocking Smad7 expression by RNA interference inhibits association of GADD34-PP1c complex with TβRI, indicating Smad7 acts as an adaptor protein in the formation of the PP1 holoenzyme that targets TβRI 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 TGFβ-induced cell cycle arrest and mediates TGFβ resistance in responding to UV light irradiation. The dephosphorylation of TβRI mediated by Smad7 is an effective mechanism for governing negative feedback in TGFβ signaling.
All Science Journal Classification (ASJC) codes
- Cell Biology