Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP
Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP
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DOI：
10.1038/ncb1209
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发表时间：
2005-01-01
影响因子：
21.3
通讯作者：
Ivaska, J
中科院分区：
文献类型：
--
作者：
Mattila, E;Pellinen, T;Ivaska, J
整合素介导的细胞粘附调节多种细胞反应，包括增殖、存活和不同细胞信号传导途径之间的串扰（1）。到目前为止，整合素主要显示出传递允许信号，从而实现锚定依赖性受体酪氨酸激酶信号传导（2-4）。在这里，我们表明，胶原结合整合素α（1）β（1）的功能作为一个负调节表皮生长因子受体（EGFR）信号通过激活蛋白酪氨酸磷酸酶。α 1整联蛋白的胞质尾区选择性地与广泛表达的蛋白酪氨酸磷酸酶TCPTP（T细胞蛋白酪氨酸磷酸酶）相互作用，并在细胞粘附于胶原蛋白后激活它。这种激活导致EGF刺激后EGFR磷酸化减少。将α 1胞质结构域肽引入细胞中诱导磷酸酶活化并抑制EGF诱导的细胞增殖和恶性细胞的锚定非依赖性生长。这些数据是TCPTP活性在体内调节的第一个证明，并代表了一个新的整合素介导的受体酪氨酸激酶信号负调控的分子范例。
Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and crosstalk between different cellular signalling pathways(1). So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling(2-4). Here we show that a collagen-binding integrin alpha(1)beta(1) functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of a 1 integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen. The activation results in reduced EGFR phosphorylation after EGF stimulation. Introduction of the a 1 cytoplasmic domain peptide into cells induces phosphatase activation and inhibits EGF-induced cell proliferation and anchorage-independent growth of malignant cells. These data are the first demonstration of the regulation of TCPTP activity in vivo and represent a new molecular paradigm of integrin-mediated negative regulation of receptor tyrosine kinase signalling.