Remy Ingrid, Montmarquette Annie, Michnick Stephen W
Département de Biochimie, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, Québec H3C 3J7, Canada.
Nat Cell Biol. 2004 Apr;6(4):358-65. doi: 10.1038/ncb1113. Epub 2004 Mar 28.
Transforming growth factor beta (TGF-beta) has a major role in cell proliferation, differentiation and apoptosis in many cell types. Integration of the TGF-beta pathway with other signalling cascades that control the same cellular processes may modulate TGF-beta responses. Here we report the discovery of a new functional link between TGF-beta and growth factor signalling pathways, mediated by a physical interaction between the serine-threonine kinase PKB (protein kinase B)/Akt and the transcriptional activator Smad3. Formation of the complex is induced by insulin, but inhibited by TGF-beta stimulation, placing PKB-Smad3 at a point of convergence between these two pathways. PKB inhibits Smad3 by preventing its phosphorylation, binding to Smad4 and nuclear translocation. In contrast, Smad3 does not inhibit PKB. Inhibition of Smad3 by PKB occurs through a kinase-activity-independent mechanism, resulting in a decrease in Smad3-mediated transcription and protection of cells against TGF-beta-induced apoptosis. Consistently, knockdown of the endogenous PKB gene with small-interfering RNA (siRNA) has the opposite effect. Our results suggest a very simple mechanism for the integration of signals arising from growth-factor- and TGF-beta-mediated pathways.
转化生长因子β（TGF-β）在多种细胞类型的细胞增殖、分化和凋亡过程中发挥着重要作用。TGF-β信号通路与控制相同细胞过程的其他信号级联的整合可能会调节TGF-β反应。在此，我们报告发现了TGF-β与生长因子信号通路之间一种新的功能联系，该联系由丝氨酸 - 苏氨酸激酶PKB（蛋白激酶B）/Akt与转录激活因子Smad3之间的物理相互作用介导。复合物的形成由胰岛素诱导，但受TGF-β刺激抑制，这使得PKB - Smad3处于这两条通路的交汇点。PKB通过阻止Smad3的磷酸化、与Smad4结合及核转位来抑制Smad3。相反，Smad3不抑制PKB。PKB对Smad3的抑制通过一种不依赖激酶活性的机制发生，导致Smad3介导的转录减少，并保护细胞免受TGF-β诱导的凋亡。同样，用小干扰RNA（siRNA）敲低内源性PKB基因会产生相反的效果。我们的结果提示了一种非常简单的机制，用于整合由生长因子和TGF-β介导的信号通路产生的信号。
