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Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis

Nature Cell Biology volume 6, pages 366–372 (2004)Cite this article

Abstract

Transforming growth factor β (TGF-β) induces both apoptosis and cell-cycle arrest in some cell lines, but only growth arrest in others1. It is not clear how this differential response to TGF-β is specified. Smad proteins are critical mediators of TGF-β signalling. After stimulation by TGF-β, Smad2 and Smad3 become phosphorylated by the activated TGF-β receptor kinases, oligomerize with Smad4, translocate to the nucleus and regulate the expression of TGF-β target genes1,2,3,4,5. Here we report that the sensitivity to TGF-β-induced apoptosis is regulated by crosstalk between the Akt/PKB serine/threonine kinase and Smad3 through a mechanism that is independent of Akt kinase activity. Akt interacts directly with unphosphorylated Smad3 to sequester it outside the nucleus, preventing its phosphorylation and nuclear translocation. This results in inhibition of Smad3-mediated transcription and apoptosis. Furthermore, the ratio of Smad3 to Akt correlates with the sensitivity of cells to TGF-β-induced apoptosis. Alteration of this ratio changes the apoptotic, but not the growth-inhibitory, responses of cells to TGF-β. These findings identify an important determinant of sensitivity to TGF-β-induced apoptosis that involves crosstalk between the TGF-β and phosphatidylinositol-3-OH kinase (PI(3)K) pathways.

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Figure 1: Akt interacts with Smad3.
Figure 2: Akt inhibits Smad3 signalling.
Figure 3: Akt sequesters Smad3 to prevent its phosphorylation and nuclear translocation.
Figure 4: The ratio of Smad3 to Akt determines the sensitivity to TGF-β-induced apoptosis.

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Acknowledgements

We thank S. Michnick for the Akt1 cDNA, A. Moustakas for anti-phospho-Smad3 antibody, and Q. Zhou for critical reading of the manuscript. This work was supported by the Human Frontier Science Program Research Grant, American Cancer Society Research Scholar grant DOE-OBER Grant to K.L., and NIH R01 and P01 grants to T.C.K. A.R.C. is supported by a predoctoral fellowship from the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, and Life Sciences Division, University of California, Berkeley, Lawrence Berkeley National Laboratory, Berkeley, 94720, CA, USA

    Andrew R. Conery & Kunxin Luo

  2. Department of Surgery, The University of Texas Medical Branch, Galveston, 77555, TX, USA

    Yanna Cao, Courtney M. Townsend Jr & Tien C. Ko

  3. Mayo Cancer Center, Jacksonville, 32224, FL, USA

    E. Aubrey Thompson

  4. Department of Human Biological Chemistry and Genetics and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, 77555, TX, USA

    Tien C. Ko

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Correspondence to Tien C. Ko or Kunxin Luo.

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Conery, A., Cao, Y., Thompson, E. et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis. Nat Cell Biol 6, 366–372 (2004). https://doi.org/10.1038/ncb1117

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