Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation at Ser411 in vascular smooth muscle cells -: Possible requirement of epidermal growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt
Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation at Ser411 in vascular smooth muscle cells -: Possible requirement of epidermal growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt
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DOI：
10.1074/jbc.274.52.36843
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发表时间：
1999-12-24
影响因子：
4.8
通讯作者：
Inagami, T
中科院分区：
文献类型：
--
作者：
Eguchi, S;Iwasaki, H;Inagami, T
生长因子激活p70 S6激酶（p70（S6 K））需要多个信号输入，包括磷酸肌醇3-激酶（PI 3 K）、其效应物Akt和使聚集在其自身抑制结构域的Ser/Thr残基（Ser（411）、Ser（418）、Ser（424）和Thr（421））磷酸化的未鉴定的激酶。然而，G蛋白偶联受体激活p70（S6 K）的机制在很大程度上仍然不确定。通过使用血管平滑肌细胞，我们已经证明Ras/细胞外信号调节激酶（ERK）通过Ca 2+依赖性激活，表皮生长因子（EGF）受体通过G（q）偶联血管紧张素II（Ang II）受体反式激活，我们提出了一个独特的串扰所需的Ser（411）磷酸化的p70（S6 K）的血管紧张素II。Ang II引起的p70（S6 K）Ser（411）和Akt Ser（473）磷酸化似乎涉及EGF受体的反式激活，并被显性负性Ras抑制，而p70（S6 K）和ERK的磷酸化对MEK抑制剂敏感，而Akt的磷酸化不敏感。相比之下，p70（S6 K）和Akt的磷酸化对PI 3 K抑制剂敏感，但ERK不敏感。观察到EGF对这些磷酸化位点的类似抑制模式，而不是胰岛素。结合显性负性Ras和MEK抑制剂对Ang II诱导的p70（S6 K）激活的抑制，我们得出结论，Ang II诱导的p70（S6 K）激活需要ERK级联和PI 3 K/Akt级联，其在EGF受体依赖性Ras激活点处分叉。
Activation of p70 S6 kinase (p70(S6K)) by growth factors requires multiple signal inputs involving phosphoinositide 3-kinase (PI3K), its effector Akt, and an unidentified kinase that phosphorylates Ser/Thr residues (Ser(411), Ser(418), Ser(424), and Thr(421)) clustered at its autoinhibitory domain. However, the mechanism by which G protein-coupled receptors activate p70(S6K) remains largely uncertain, By using vascular smooth muscle cells in which we have demonstrated Ras/extracellular signal-regulated kinase (ERK) activation through Ca2+- dependent, epidermal growth factor (EGF) receptor transactivation by G(q)-coupled angiotensin II (Ang II) receptor, we present a unique cross-talk required for Ser(411) phosphorylation of p70(S6K) by Ang II. Both p70(S6K) Ser(411) and Akt Ser(473) phosphorylation by Ang II appear to involve EGF receptor transactivation and were inhibited by dominant-negative Ras, whereas the phosphorylation of p70(S6K) and ERK but not Akt was sensitive to the MEK inhibitor. By contrast, the phosphorylation of p70(S6K) and Akt but not ERK was sensitive to PI3K inhibitors. Similar inhibitory pattern on these phosphorylation sites by EGF but not insulin was observed. Taken together with the inhibition of Ang II-induced p70(S6K) activation by dominant-negative Ras and the MEK inhibitor, we conclude that Ang II-initiated activation of p70(S6K) requires both ERK cascade and PI3K/Akt cascade that bifurcate at the point of EGF receptor-dependent Ras activation.