Replacement of tyrosine 1251 in the carboxyl terminus of the insulin-like growth factor-I receptor disrupts the actin cytoskeleton and inhibits proliferation and anchorage-independent growth
Replacement of tyrosine 1251 in the carboxyl terminus of the insulin-like growth factor-I receptor disrupts the actin cytoskeleton and inhibits proliferation and anchorage-independent growth
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DOI：
10.1074/jbc.273.29.18411
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发表时间：
1998-07-17
影响因子：
4.8
通讯作者：
LeRoith, D
中科院分区：
文献类型：
--
作者：
Blakesley, VA;Koval, AP;LeRoith, D
胰岛素样生长因子（IGF）-I信号通过IGF-I受体调节细胞的粘附和增殖以及过表达IGF-I受体的细胞的转化能力。细胞内蛋白质的酪氨酸磷酸化对于IGF-I诱导的促有丝分裂和致肿瘤信号的转导是必不可少的。IGF-I诱导特定的细胞骨架结构和相关黏着斑复合物中蛋白质的磷酸化。确定IGF-I受体参与介导这些信号的确切途径将极大地有助于了解IGF-I的作用。我们以前已经表明，取代酪氨酸残基1250和1251在羧基末端的IGF-I受体废除IGF-I诱导的细胞增殖和裸鼠肿瘤形成。在这项研究中，酪氨酸1250或1251的替代同样降低了细胞以锚定非依赖性方式生长的能力。肌动蛋白细胞骨架和黏着斑蛋白的细胞定位被酪氨酸1251的取代破坏，酪氨酸残基1250和1251对于两种已知底物（胰岛素受体底物-1和SHC）的酪氨酸磷酸化不是必需的，也不是已知下游衔接蛋白与这些底物的缔合。此外，这些突变型IGF-I受体不影响IGF-I刺激的p42/p44促分裂原活化蛋白激酶活化或磷脂酰肌醇（PI）3 '-激酶活性。因此，似乎在表达酪氨酸1250和1251突变型IGF-I受体的成纤维细胞中，影响有丝分裂和肿瘤发生的信号转导途径并不完全通过PI 3 '-激酶或有丝分裂原活化蛋白激酶途径发生。
Insulin-like growth factor (IGF)-I signaling through the IGF-I receptor modulates cellular adhesion and proliferation and the transforming ability of cells overexpressing the IGF-I receptor. Tyrosine phosphorylation of intracellular proteins is essential for this transduction of the IGF-I-induced mitogenic and tumorigenic signals. IGF-I induces specific cytoskeletal structure and the phosphorylation of proteins in the associated focal adhesion complexes. The determination of the exact pathways emanating from the IGF-I receptor that are involved in mediating these signals will contribute greatly to the understanding of IGF-I action. We have previously shown that replacement of tyrosine residues 1250 and 1251 in the carboxyl terminus of the IGF-I receptor abrogates IGF-I-induced cellular proliferation and tumor formation in nude mice. In this study, replacement of either tyrosine 1250 or 1251 similarly re duces the cells ability to grow in an anchorage-independent manner. The actin cytoskeleton and cellular localization of vinculin are disrupted by replacement of tyrosine 1251, Tyrosine residues 1250 and 1251 are not essential for tyrosine phosphorylation of two known substrates; insulin receptor substrate-1 and SHC, nor association of known downstream adaptor proteins to these substrates. In addition, these mutant IGF-I receptors do not affect IGF-I-stimulated p42/p44 mitogen-activated protein kinase activation or phosphatidylinositol (PI) 3'-kinase activity. Thus, it appears that in fibroblasts expressing tyrosine 1250 and 1251 mutant IGF-I receptors, the signal transduction pathways impacting on mitogenesis and tumorigenesis do not occur exclusively through the PI 3'-kinase or mitogen-activated protein kinase pathways.