IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase
IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase
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DOI：
10.1152/ajpgi.00310.2002
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发表时间：
2003-03-01
影响因子：
4.5
通讯作者：
Kuemmerle, JF
中科院分区：
文献类型：
--
作者：
Kuemmerle, JF
内源性IGF-I通过联合激活磷脂酰肌醇3-激酶(PI3K)和ERK1/2来调节人肠道平滑肌细胞的生长。70 kDa的核糖体S6激酶(P70S6)是由几个独立调节的激酶激活的细胞生长的关键调节因子。本研究探讨了p70S6蛋白在IGF-I诱导的人肠道平滑肌细胞生长中的作用，并初步探讨了p70S6蛋白的激活机制。IGF-I通过PI3K或ERK1/2途径诱导的生长需要激活p70S6激酶。IGF-I诱导的PI3K、3-磷酸肌醇依赖的激酶-1(PDK-1)和p70S6的激活呈浓度依赖关系，并遵循相似的时间进程。IGF-I对Thr(421)/Ser(424)、Thr(389)和Thr(229)p70S6蛋白的磷酸化具有时间和浓度依赖性，与p70S6蛋白的激活平行。P70S6蛋白(Thr(421)/Ser(424))的磷酸化依赖于PI3K，不依赖于PDK-1，而p70S6蛋白(Thr(389))和p70S6蛋白(Thr(229))的磷酸化和活化则依赖于PI3K和PDK-1。IGF-I可依次诱导Akt(Ser(308))、Akt(Ser(473))和哺乳动物靶标雷帕霉素(Ser(2448))的磷酸化；然而，将不具有激酶活性的Akt1(K179M)转染肌肉细胞，表明IGF-I激活p70S6激酶和刺激人肠道肌细胞增殖并不是这些事件所必需的。
Endogenous IGF-I regulates growth of human intestinal smooth muscle cells by jointly activating phosphatidylinositol 3-kinase (PI3K) and ERK1/2. The 70-kDa ribosomal S6 kinase (p70S6 kinase) is a key regulator of cell growth activated by several independently regulated kinases. The present study characterized the role of p70S6 kinase in IGF-I-induced growth of human intestinal smooth muscle cells and identified the mechanisms of p70S6 kinase activation. IGF-I-induced growth elicited via either the PI3K or ERK1/2 pathway required activation of p70S6 kinase. IGF-I elicited concentration-dependent activation of PI3K, 3-phosphoinositide-dependent kinase-1 (PDK-1), and p70S6 kinase that was sequential and followed similar time courses. IGF-I caused time-dependent and concentration-dependent phosphorylation of p70S6 kinase on Thr(421)/Ser(424), Thr(389), and Thr(229) that paralleled p70S6 kinase activation. p70S6 kinase(Thr(421) /Ser(424)) phosphorylation was PI3K dependent and PDK-1 independent, whereas p70S6 kinase( Thr(389)) and p70S6 kinase(Thr(229)) phosphorylation and p70S6 kinase activation were PI3K dependent and PDK-1 dependent. IGF-I elicited sequential Akt(Ser(308)), Akt(Ser(473)), and mammalian target of rapamycin(Ser(2448)) phosphorylation; however, transfection of muscle cells with kinase-inactive Akt1(K179M) showed that these events were not required for IGF-I to activate p70S6 kinase and stimulate proliferation of human intestinal muscle cells.