Zhang Lizhi, Duan Chao Jun, Binkley Charles, Li Gangyong, Uhler Michael D, Logsdon Craig D, Simeone Diane M
Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Mol Cell Biol. 2004 Mar;24(5):2169-80. doi: 10.1128/MCB.24.5.2169-2180.2004.
Transforming growth factor beta (TGFbeta) interacts with cell surface receptors to initiate a signaling cascade critical in regulating growth, differentiation, and development of many cell types. TGFbeta signaling involves activation of Smad proteins which directly regulate target gene expression. Here we show that Smad proteins also regulate gene expression by using a previously unrecognized pathway involving direct interaction with protein kinase A (PKA). PKA has numerous effects on growth, differentiation, and apoptosis, and activation of PKA is generally initiated by increased cellular cyclic AMP (cAMP). However, we found that TGFbeta activates PKA independent of increased cAMP, and our observations support the conclusion that there is formation of a complex between Smad proteins and the regulatory subunit of PKA, with release of the catalytic subunit from the PKA holoenzyme. We also found that the activation of PKA was required for TGFbeta activation of CREB, induction of p21(Cip1), and inhibition of cell growth. Taken together, these data indicate an important and previously unrecognized interaction between the TGFbeta and PKA signaling pathways.
转化生长因子β（TGFβ）与细胞表面受体相互作用，启动一个对多种细胞类型的生长、分化和发育至关重要的信号级联反应。TGFβ信号传导涉及Smad蛋白的激活，而Smad蛋白直接调节靶基因的表达。在此我们表明，Smad蛋白还通过一条先前未被认识的途径调节基因表达，该途径涉及与蛋白激酶A（PKA）的直接相互作用。PKA对生长、分化和细胞凋亡有多种影响，PKA的激活通常由细胞内环磷酸腺苷（cAMP）增加引发。然而，我们发现TGFβ独立于cAMP增加而激活PKA，并且我们的观察结果支持以下结论：Smad蛋白与PKA的调节亚基之间形成了复合物，催化亚基从PKA全酶中释放出来。我们还发现，PKA的激活是TGFβ激活CREB、诱导p21（Cip1）以及抑制细胞生长所必需的。综上所述，这些数据表明TGFβ和PKA信号通路之间存在一种重要且先前未被认识的相互作用。
