TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest

On TGF-beta binding, the TGF-beta receptor directly phosphorylates and acti vates the transcription factors Smad2/3, leading to G(1) arrest. Here, we p resent evidence for a second, parallel, TGF-beta -dependent pathway for cel l cycle arrest, achieved via inhibition of p70(s6k). TGF-beta induces assoc iation of its receptor with protein phosphatase-2A (PP2A)-B alpha. Concomit antly, three PP2A-subunits, B alpha, A beta, and C alpha, associate with p7 0(s6k), leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G(1) arrest, abrogation of both, the inhibi tion of p70(s6k), and transcription through Smad proteins is required for r elease of epithelial cells from TGF-beta -induced G(1) arrest. TGF-beta the reby modulates the translational and posttranscriptional control of cell cy cle progression.