Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y Y, Grinnell B W, Richardson M A, Topper J N, Gimbrone M A, Wrana J L, Falb D
Division of Gastroenterology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Cell. 1997 Jun 27;89(7):1165-73. doi: 10.1016/s0092-8674(00)80303-7.
TGFbeta signaling is initiated when the type I receptor phosphorylates the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, and regulation of transcriptional responses. Here we demonstrate that Smad7 is an inhibitor of TGFbeta signaling. Smad7 prevents TGFbeta-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfere with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellular antagonists of the type I kinase domain of TGFbeta family receptors.
当I型受体使MAD相关蛋白Smad2的C末端丝氨酸残基磷酸化时，转化生长因子β（TGFβ）信号传导被启动。这导致Smad2与Smad4结合，转位至细胞核，并调节转录反应。在此我们证明Smad7是TGFβ信号传导的抑制剂。Smad7可阻止TGFβ依赖性的Smad2/Smad4复合物的形成，并抑制Smad2的核内积累。Smad7与活化的TGFβ I型受体稳定相互作用，从而阻断Smad2的结合、磷酸化及激活。此外，干扰受体结合的Smad7突变会破坏其抑制活性。因此，这些研究确定了MAD相关蛋白作为TGFβ家族受体I型激酶结构域的细胞内拮抗剂的新功能。
