The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation.
The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation.
复制标题
激酶缺陷的 Src 作为 Cbl 磷酸化的 Abl 激酶的抑制剂。
DOI：
10.1073/pnas.060030697
复制
发表时间：
2000
影响因子：
11.1
通讯作者：
Hanafusa,H
中科院分区：
文献类型：
--
作者：
Shishido,T;Akagi,T;Ouchi,T;Georgescu,MM;Langdon,WY;Hanafusa,H
已知 Abl 的激酶活性受到与 Abl 的 Src 同源 (SH) 3 结构域相互作用的推定反式作用抑制剂分子的调节。在此，我们报道激酶缺陷型 Src (SrcKD) 直接抑制 Abl 对 Cbl 和其他细胞蛋白的酪氨酸磷酸化。我们发现 SrcKD 的 SH2 和 SH3 结构域对于 Abl 激酶磷酸化 Cbl 的抑制活性是必需的。为了抑制 Abl 对 Cbl 的磷酸化，需要 SrcKD 的 SH3 结构域和 Cbl 之间的相互作用。 SrcKD 和 Cbl 之间的这种相互作用是由 Cbl 的封闭结构调节的。 Abl 与 Cbl 末端羧基末端区域的结合揭示了 SrcKD 与 Cbl 的结合位点。这导致了三元复合物通过空间位阻抑制 Abl 介导的 Cbl 磷酸化。这些结果说明了酶失活的 Src 在体内发挥生物学功能的机制。
The kinase activity of Abl is known to be regulated by a putative trans-acting inhibitor molecule interacting with the Src homology (SH) 3 domain of Abl. Here we report that the kinase-deficient Src (SrcKD) directly inhibits the tyrosine phosphorylation of Cbl and other cellular proteins by Abl. We found that both the SH2 and SH3 domains of SrcKD are necessary for the suppressor activity toward the Abl kinase phosphorylating Cbl. To suppress the Cbl phosphorylation by Abl, the interaction between the SH3 domain of SrcKD and Cbl is required. This interaction between SrcKD and Cbl is regulated by a closed structure of Cbl. The binding of Abl to the extreme carboxyl-terminal region of Cbl unmasks the binding site of SrcKD to Cbl. This results in a ternary complex that inhibits the Abl-mediated phosphorylation of Cbl by steric hindrance. These results illustrate a mechanism by which the enzymatically inactive Src can exert a biological functionin vivo.