Signal Crosstalk

PKB as Interpathway Connector

Science's STKE  06 Apr 2004:
Vol. 2004, Issue 227, pp. tw122
DOI: 10.1126/stke.2272004tw122

The apoptosis-inducing effects of transforming growth factor-β (TGF-β) are antagonized by signals from receptor tyrosine kinase growth factor receptors, such as the insulin receptor. Two papers this week show that such effects of insulin are mediated by direct interaction of protein kinase B (PKB, also called Akt) with the transcriptional activator Smad3. Oddly enough, this effect of PKB does not require kinase activity of the enzyme; rather, it appears to result from the physical interaction and consequent sequestration of Smad3 outside of the nucleus. In various mammalian cell lines, Conery et al. and Remy et al. showed that Smad3 and PKB interacted and that treatment of cells with insulin enhanced the association of the proteins, whereas treatment with TGF-β inhibited it. Transcription dependent on transfected Smad3 was inhibited when cells were also transfected with PKB. Kinase activity of PKB appeared not to be required, though, because catalytically inactive mutants of PKB also inhibited Smad3-dependent transcription or TGF-β-induced apoptosis. Immunostaining of cultured cells confirmed that, after insulin treatment, PKB was localized to the plasma membrane. Smad3 is normally cytoplasmic and moves to the nucleus in cells treated with TGF-β. However, in cells exposed to insulin, Smad3 was localized with PKB at the membrane and failed to accumulate in the nucleus. The inhibitory effects of PKB appear to be specific and still allow TGF-β to inhibit cell growth through activation of Smad2. In fact, Conery et al. provide evidence that it is the ratio of the amount of Smad3 to that of PKB that determines whether a cell will respond to TGF-β by suspending cell proliferation or by undergoing cell death.

A. R. Conery, Y. Cao, E. A. Thompson, C. M. Townsend Jr, T. C. Ko, K. Luo, Akt interacts directly with Smad3 to regulate the sensitivity to TGF-β-induced apoptosis. Nat. Cell Biol. 6, 366-372 (2004). [Online Journal]

I. Remy, A. Montmarquette, S. W. Michnick, PKB/Akt modulates TGF-β signalling through a direct interaction with Smad3. Nat. Cell Biol. 6, 358-365 (2004). [Online Journal]