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首页> 外文期刊>American Journal of Physiology >Occupation of alphavbeta3-integrin by endogenous ligands modulates IGF-I receptor activation and proliferation of human intestinal smooth muscle.
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Occupation of alphavbeta3-integrin by endogenous ligands modulates IGF-I receptor activation and proliferation of human intestinal smooth muscle.

机译：内源性配体对αvbeta3-整联蛋白的占领可调节IGF-I受体的活化和人肠平滑肌的增殖。

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摘要

We have previously shown that endogenous IGF-I regulates growth of human intestinal smooth muscle cells by stimulating proliferation and inhibiting apoptosis. In active Crohn's disease, expression of IGF-I and the alpha(v)beta(3)-integrin receptor ligands fibronectin and vitronectin is increased. The aim of the present study was to determine whether occupation of the alpha(v)beta(3)-receptor influences IGF-I receptor tyrosine kinase activation and function in human intestinal smooth muscle cells. In untreated cells, IGF-I elicited time-dependent tyrosine phosphorylation of its cognate receptor that was maximal within 2 min and sustained for 30 min. In the presence of the alpha(v)beta(3)-ligand fibronectin, IGF-I-stimulated IGF-I receptor activation was augmented. Conversely, in the presence of the alpha(v)beta(3)-specific disintegrin echistatin, IGF-I-stimulated IGF-I receptor tyrosine kinase phosphorylation was inhibited. IGF-I-stimulated IGF-I receptor activation was accompanied by recruitment of theadapter protein IRS-1, activation of Erk1/2, p70S6 kinase, and proliferation. These effects were augmented by fibronectin and attenuated by echistatin. IGF-I also elicited time-dependent recruitment of protein tyrosine phosphatase SHP-2 that coincided with dephosphorylation of the tyrosine phosphorylated IGF-I receptor tyrosine kinase. The alpha(v)beta(3)-disintegrin echistatin accelerated the rate of SHP-2 recruitment and deactivation of the IGF-I receptor tyrosine kinase. The results show that occupancy of the alpha(v)beta(3)-integrin receptor modulates IGF-I-induced IGF-I receptor activation and function in human intestinal muscle cells. We hypothesize that the concomitant increases in the expression of alpha(v)beta(3)-ligands and of IGF-I in active Crohn's disease may contribute to muscle hyperplasia and stricture formation by acting in concert to augment IGF-I-stimulated IGF-I receptor tyrosine kinase activity and IGF-I-mediated muscle cell growth.
机译：先前我们已经表明，内源性IGF-I通过刺激增殖和抑制细胞凋亡来调节人肠平滑肌细胞的生长。在活跃的克罗恩病中，IGF-I和alpha（v）beta（3）-整合素受体配体纤连蛋白和玻连蛋白的表达增加。本研究的目的是确定α（v）beta（3）受体的占领是否会影响人肠平滑肌细胞中的IGF-I受体酪氨酸激酶激活和功能。在未处理的细胞中，IGF-1引起其关联受体的时间依赖性酪氨酸磷酸化，该受体在2分钟内达到最大值，并持续30分钟。在存在alpha（v）beta（3）-配体纤连蛋白的情况下，IGF-I刺激的IGF-I受体激活增加。相反，在存在alpha（v）beta（3）-特异性整联蛋白echistatin的情况下，IGF-1刺激的IGF-1受体酪氨酸激酶磷酸化受到抑制。 IGF-I刺激的IGF-I受体激活伴随有衔接蛋白IRS-1的募集，Erk1 / 2，p70S6激酶的激活和增殖。纤连蛋白增强了这些作用，而echistatin减弱了这些作用。 IGF-1还引起蛋白质酪氨酸磷酸酶SHP-2的时间依赖性募集，其与酪氨酸磷酸化的IGF-1受体酪氨酸激酶的去磷酸化相吻合。 alpha（v）beta（3）-disintegrin echistatin加快了SHP-2募集和IGF-1受体酪氨酸激酶失活的速度。结果表明，α（v）beta（3）-整合素受体的存在调节人肠肌肉细胞中IGF-I诱导的IGF-I受体的激活和功能。我们假设在活跃的克罗恩病中伴随发生的alpha（v）beta（3）-配体和IGF-I的表达增加可能通过协同作用来增强IGF-I刺激的IGF- I受体酪氨酸激酶活性和IGF-I介导的肌肉细胞生长。

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