TGF-β inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest

摘要

On TGF-β binding, the TGF-β receptor directly phosphorylates and activates the transcription factors Smad2/3, leading to G1 arrest. Here, we present evidence for a second, parallel, TGF-β-dependent pathway for cell cycle arrest, achieved via inhibition of p70^s6k. TGF-β induces association of its receptor with protein phosphatase-2A (PP2A)-Bα. Concomitantly, three PP2A-subunits, Bα, Aβ, and Cα, associate with p70^s6k, leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G1 arrest, abrogation of both, the inhibition of p70^s6k, and transcription through Smad proteins is required for release of epithelial cells from TGF-β-induced G1 arrest. TGF-β thereby modulates the translational and posttranscriptional control of cell cycle progression.