Souchelnytskyi S, ten Dijke P, Miyazono K, Heldin C H
Ludwig Institute for Cancer Research, Uppsala, Sweden.
EMBO J. 1996 Nov 15;15(22):6231-40.
Transforming growth factor-beta (TGF-beta) signals via an oligomeric complex of two serine/threonine kinase receptors denoted TGF-beta type I receptor (TbetaR-I) and type II receptor (TbetaR-II). We investigated the in vivo phosphorylation sites in TbetaR-I and TbetaR-II after complex formation. Phosphorylation of TbetaR-II was observed at residues in the C-terminus (Ser549 and Ser551) and at residues in the juxtamembrane domain (Ser223, Ser226 and Ser227). TGF-beta1 induced in vivo phosphorylation of serine and threonine residues in the juxtamembrane domain of TbetaR-I in a region rich in glycine, serine and threonine residues (GS domain; Thr185, Thr186, Ser187, Ser189 and Ser191), and more N-terminal of this region (Ser165). Phosphorylation in the GS domain has been shown previously to be involved in activation of the TbetaR-I kinase. We show here that phosphorylation of TbetaR-I at Ser165 is involved in modulation of TGF-beta1 signaling. Mutations of Ser165 in TbetaR-I led to an increase in TGF-beta1-mediated growth inhibition and extracellular matrix formation, but, in contrast, to decreased TGF-beta1-induced apoptosis. A transcriptional activation signal was not affected. Mutations of Ser165 changed the phosphorylation pattern of TbetaR-I. These observations suggest that TGF-beta receptor signaling specificity is modulated by phosphorylation of Ser165 of TbetaR-I.
转化生长因子-β（TGF-β）通过由两种丝氨酸/苏氨酸激酶受体组成的寡聚复合物来传递信号，这两种受体分别称为TGF-βⅠ型受体（TβR-Ⅰ）和Ⅱ型受体（TβR-Ⅱ）。我们研究了复合物形成后TβR-Ⅰ和TβR-Ⅱ在体内的磷酸化位点。在TβR-Ⅱ的C末端残基（Ser549和Ser551）以及近膜结构域的残基（Ser223、Ser226和Ser227）处观察到了磷酸化。TGF-β1在富含甘氨酸、丝氨酸和苏氨酸残基的区域（GS结构域；Thr185、Thr186、Ser187、Ser189和Ser191）以及该区域更靠近N端的位置（Ser165）诱导了TβR-Ⅰ近膜结构域中丝氨酸和苏氨酸残基的体内磷酸化。先前已表明GS结构域中的磷酸化参与TβR-Ⅰ激酶的激活。我们在此表明，TβR-Ⅰ的Ser165磷酸化参与TGF-β1信号的调节。TβR-Ⅰ中Ser165的突变导致TGF-β1介导的生长抑制和细胞外基质形成增加，但相反，TGF-β1诱导的细胞凋亡减少。转录激活信号不受影响。Ser165的突变改变了TβR-Ⅰ的磷酸化模式。这些观察结果表明，TGF-β受体信号特异性受TβR-Ⅰ的Ser165磷酸化调节。
