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PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3

Ingrid Remy1, Annie Montmarquette, Stephen W Michnick

  • 1Département de Biochimie, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, Québec H3C 3J7, Canada.

Nature Cell Biology
|March 30, 2004
PubMed

Insights

Protein kinase B (PKB)/Akt physically interacts with Smad3, integrating growth factor and TGF-beta signaling. PKB inhibits Smad3, decreasing TGF-beta-induced apoptosis and modulating cell responses.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Biochemistry

Background:

  • Transforming growth factor beta (TGF-beta) regulates crucial cell processes like proliferation, differentiation, and apoptosis.
  • Understanding how TGF-beta signaling integrates with other pathways is key to modulating cellular responses.

Purpose of the Study:

  • To identify and characterize a novel functional link between TGF-beta and growth factor signaling pathways.
  • To elucidate the mechanism of interaction between PKB/Akt and Smad3.

Main Methods:

  • Investigated physical interaction between PKB/Akt and Smad3.
  • Utilized insulin and TGF-beta stimulation to study complex formation.
  • Employed small-interfering RNA (siRNA) for gene knockdown of PKB.

Main Results:

  • Discovered a physical interaction between PKB/Akt and Smad3, forming a complex induced by insulin but inhibited by TGF-beta.
  • PKB/Akt inhibits Smad3 by preventing phosphorylation, Smad4 binding, and nuclear translocation.
  • PKB-mediated inhibition of Smad3 reduces Smad3-dependent transcription and protects cells from TGF-beta-induced apoptosis.

Conclusions:

  • PKB/Akt and Smad3 act as a convergence point for growth factor and TGF-beta signaling pathways.
  • PKB/Akt regulates TGF-beta responses through a kinase-activity-independent mechanism on Smad3.
  • This interaction provides a simple mechanism for integrating signals from distinct cellular pathways.

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