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

Andrew R. Conery, Yanna Cao, E Aubrey Thompson, Courtney M. Townsend, Tien C. Ko, Kunxin Luo

Research output: Contribution to journalArticle

282 Citations (Scopus)

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 genes1-5. 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.

Original languageEnglish (US)
Pages (from-to)366-372
Number of pages7
JournalNature Cell Biology
Volume6
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

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Transforming Growth Factors
Apoptosis
Phosphotransferases
Smad Proteins
Growth Factor Receptors
Protein-Serine-Threonine Kinases
Growth
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
Phosphorylation
Cell Line

ASJC Scopus subject areas

  • Cell Biology

Cite this

Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis. / Conery, Andrew R.; Cao, Yanna; Thompson, E Aubrey; Townsend, Courtney M.; Ko, Tien C.; Luo, Kunxin.

In: Nature Cell Biology, Vol. 6, No. 4, 04.2004, p. 366-372.

Research output: Contribution to journalArticle

Conery, Andrew R. ; Cao, Yanna ; Thompson, E Aubrey ; Townsend, Courtney M. ; Ko, Tien C. ; Luo, Kunxin. / Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis. In: Nature Cell Biology. 2004 ; Vol. 6, No. 4. pp. 366-372.
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