Positive and negative regulation of type II TGF beta receptor signal transduction by autophosphorylation on multiple serine residues
Positive and negative regulation of type II TGF beta receptor signal transduction by autophosphorylation on multiple serine residues
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DOI：
10.1093/emboj/16.8.1970
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发表时间：
1997-04-15
期刊：
影响因子：
11.4
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Luo, KX;Lodish, HF
II型转化生长因子- β (tgf - β)受体丝氨酸/苏氨酸激酶（T β RII）负责启动多种tgf - β信号通路，其功能的丧失与许多类型的人类癌症有关。在这里，我们发现T β RII激酶受到至少三个丝氨酸残基上的自磷酸化的复杂调节，在激酶结构域外的膜近端段的Ser213，经历分子内的自磷酸化，这对于T β RII激酶活性的激活，T β RI的激活和tgf - β诱导的生长抑制是必不可少的。相反，Ser409和Ser416位于蛋白激酶三维结构模型中与底物识别T环区相对应的片段，其磷酸化可通过受体二聚化增强，并可通过分子间机制发生。Ser409的磷酸化对T β RII激酶信号传导至关重要，而Ser416的磷酸化则抑制受体功能。Ser416向丙氨酸的突变导致一个过度活跃的受体，比野生型更能诱导T β RI激活和随后的细胞周期阻滞。由于在单个受体上，Ser409或Ser416可以发生自磷酸化，但不能同时发生这两种磷酸化，因此我们的研究结果表明，T β RII磷酸化受到复杂的调控，并对tgf - β受体信号转导产生积极和消极的影响。
The type II transforming growth factor-beta (TGF-beta) receptor Ser/Thr kinase (T beta RII) is responsible for the initiation of multiple TGF-beta signaling pathways, and loss of its function is associated with many types of human cancer. Here we show that T beta RII kinase is regulated intricately by autophosphorylation on at least three serine residues, Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of T beta RII kinase activity, activation of T beta RI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism, Phosphorylation of Ser409 is essential for T beta RII kinase signaling, while phosphorylation of Ser416 inhibits receptor function, Mutation of Ser416 to alanine results in a hyperactive receptor that is better able than wild-type to induce T beta RI activation and subsequent cell cycle arrest. Since on a single receptor either Ser409 or Ser416, but not both simultaneously, can become autophosphorylated, our results show that T beta RII phosphorylation is regulated intricately and affects TGF-beta receptor signal transduction both positively and negatively.