Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins.
Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins.
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1型胰岛素样生长因子受体信号传导和功能的选择性调节。
DOI：
10.1083/jcb.200403003
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发表时间：
2004-08-02
影响因子：
7.8
通讯作者：
Languino, Lucia R
中科院分区：
文献类型：
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作者：
Goel, Hira Lal;Fornaro, Mara;Moro, Loredana;Teider, Natalia;Rhim, Johng S;King, Michael;Languino, Lucia R
我们在这里表明，β1整合素选择性地调节胰岛素样生长因子I型受体（IGF- ir）信号，以响应IGF刺激。β1A整合素与IGF-IR和胰岛素受体底物-1 （IRS-1）形成复合物；该复合物不促进igf - 1介导的细胞粘附层粘连蛋白（LN），尽管它确实支持igf - 1介导的细胞增殖。相反，β1C，一种整合素细胞质变体，在IGF-I的作用下增加细胞对LN的粘附，而其被核酶下调可阻止igf介导的LN粘附。此外，β1C通过抑制IGF-IR在IGF-I刺激下的自磷酸化，完全阻止了igf介导的细胞增殖和肿瘤生长。有证据表明，β1细胞结构域在介导β1整合素与IRS-1或grb2相关结合物1 (Gab1)/含sh2蛋白酪氨酸磷酸2 （Shp2）的结合中起重要作用，后者是IGF-IR的下游效应物：具体而言，β1A与IRS-1和β1C与Gab1/Shp2相关。本研究揭示了一种由整合素细胞质域介导的新机制，该机制在IGF的作用下差异调节细胞对LN的粘附和细胞增殖。
We show here that β1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The β1A integrin forms a complex with the IGF-IR and insulin receptor substrate-1 (IRS-1); this complex does not promote IGF-I mediated cell adhesion to laminin (LN), although it does support IGF-mediated cell proliferation. In contrast, β1C, an integrin cytoplasmic variant, increases cell adhesion to LN in response to IGF-I and its down-regulation by a ribozyme prevents IGF-mediated adhesion to LN. Moreover, β1C completely prevents IGF-mediated cell proliferation and tumor growth by inhibiting IGF-IR auto-phosphorylation in response to IGF-I stimulation. Evidence is provided that the β1 cytodomain plays an important role in mediating β1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, β1A associates with IRS-1 and β1C with Gab1/Shp2. This study unravels a novel mechanism mediated by the integrin cytoplasmic domain that differentially regulates cell adhesion to LN and cell proliferation in response to IGF.