Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the α6β4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion
Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the α6β4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion
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DOI：
10.1128/mcb.21.15.5082-5093.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Shaw, LM
中科院分区：
文献类型：
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作者：
Shaw, LM
α 6 β 4整合素的表达通过激活磷酸肌苷3-OH激酶（PI3K）的机制增加了癌细胞的侵袭潜力。在本研究中，我们研究了α 6 β 4整合素激活PI3K的信号通路，α 6和β 4细胞质结构域都不包含PI3K的一致结合基序pYMXR I，这表明α 6 β 4整合素激活这种脂质激酶可能涉及其他蛋白。我们鉴定了胰岛素受体底物1 （IRS-1）和IRS-2作为α 6 β 4整合素激活PI3K的信号中间体。IRS-1和IRS-2是细胞质适配器蛋白，它们不包含内在的激酶活性，而是通过将蛋白质募集到表面受体，在那里它们组织信号复合物而起作用。通过共免疫沉淀确定，α 6 β 4受体的连接可促进IRS-1和IRS-2的酪氨酸磷酸化，并增加其与PI3K的关联。此外，我们在beta4亚基的细胞质区域发现了一个酪氨酸残基Y1494，它是α 6 beta4依赖的IRS-2磷酸化和PI3K激活所必需的，以响应受体连接。最重要的是，Y1494对于α 6 beta4整合素促进癌症侵袭的能力至关重要。综上所述，这些结果表明TRS蛋白在alpha6 β - 4依赖性促进肿瘤侵袭中发挥了关键作用。
Expression of the alpha6 beta4 integrin increases the invasive potential of carcinoma cells by a mechanism that involves activation of phosphoinositide 3-OH kinase (PI3K). In the present study, we investigated the signaling pathway by which the alpha6 beta4 integrin activates PI3K Neither the alpha6 nor the beta4 cytoplasmic domain contains the consensus binding motif for PI3K, pYMXR I, indicating that additional proteins are likely to be involved in the activation of this lipid kinase by the alpha6 beta4 integrin, We identified insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the activation of PI3K by the alpha6 beta4 integrin, IRS-1 and IRS-2 are cytoplasmic adapter proteins that do not contain intrinsic kinase activity but rather function by recruiting proteins to surface receptors, where they organize signaling complexes. Ligation of the alpha6 beta4 receptor promotes tyrosine phosphorylation of IRS-1 and IRS-2 and increases their association with PI3K, as determined by coimmunoprecipitation. Moreover, we identified a tyrosine residue in the cytoplasmic domain of the beta4 subunit, Y1494, that is required for alpha6 beta4-dependent phosphorylation of IRS-2 and activation of PI3K in response to receptor ligation, Most importantly, Y1494 is essential for the ability of the alpha6 beta4 integrin to promote carcinoma invasion. Taken together, these results imply a key role for the TRS proteins in the alpha6 beta4-dependent promotion of carcinoma invasion.