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

Claudia Petritsch; Hartmut Beug; Allan Balmain; Martin Oft

doi:10.1101/gad.854200

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

¹IMP, Research Institute for Molecular Pathology, A-1030 Vienna, Austria; ²University of California San Francisco Cancer Center, San Francisco, California 94143, USA, and Onyx Pharmaceuticals, Richmond, California 94801, USA

Abstract

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.

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Footnotes

↵3 Present address: Howard Hughes Medical Institute, UCSF, San Francisco, CA 94143, USA.
↵4 Corresponding author.
E-MAIL moft{at}cc.ucsf.edu; FAX (415) 502-6779.
Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.854200.
- Received September 26, 2000.
- Accepted October 27, 2000.
Cold Spring Harbor Laboratory Press