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

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 p70s6k. TGF-β induces association of its receptor with protein phosphatase-2A (PP2A)-Bα. Concomitantly, three PP2A-subunits, Bα, Aβ, and Cα, associate with p70s6k, leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G1 arrest, abrogation of both, the inhibition of p70s6k, 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.