Editors' ChoiceTranscription

Smads' Alternate Route to Genes

Science's STKE  24 Feb 2004:
Vol. 2004, Issue 221, pp. tw68-TW68
DOI: 10.1126/stke.2212004TW68

The secreted factor transforming growth factor-β (TGF-β) and the cytosolic enzyme protein kinase A (PKA) regulate similar biological processes, such as cell growth and differentiation, but have never been implicated in the same signaling pathway. Zhang et al. have now uncovered a mechanism by which TGF-β activates PKA in cultured mouse cells. TGF-β association with its cognate receptor at the cell surface results in the phosphorylation and dissociation of a Smad molecule from the receptor, followed by dimerization with cytosolic Smad4 and translocation of the heterodimer into the nucleus to regulate gene expression. The study shows that, in cells treated with TGF-β, Smad3 becomes phosphorylated and then combines with Smad4. The Smad3-Smad4 complex then associates with the regulatory subunits of PKA, which causes the release and deployment of the PKA catalytic subunits to the nucleus to control transcription. This effect was not observed in Smad4-deficient cells but did occur in the absence of an increase in intracellular cAMP, the major known activator of PKA. However, purified recombinant Smad proteins and the regulatory or catalytic subunits of PKA did not interact in vitro, which suggests that other proteins are required for their functional interaction in vivo. The TGF-β-PKA signaling pathway activated the transcription factor CREB, a known critical regulator of cell proliferation and differentiation.

L. Zhang, C. J. Duan, C. Brinkley, G. Li, M. D. Uhler, C. D. Logsdon, D. M. Simeone, A transforming growth factor β-induced Smad3/Smad4 complex directly activates protein kinase A. Mol. Cell. Biol. 24, 2169-2180 (2004). [Online Journal]