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表皮生长因子受体依赖性调节整合素介导的信号传导及上皮细胞进入细胞周期。

Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells.

作者信息

Bill Heather M, Knudsen Beatrice, Moores Sheri L, Muthuswamy Senthil K, Rao Vikram R, Brugge Joan S, Miranti Cindy K

机构信息

Van Andel Research Institute, 333 Bostwick Ave., SE, Grand Rapids, MI 49503, USA.

出版信息

Mol Cell Biol. 2004 Oct;24(19):8586-99. doi: 10.1128/MCB.24.19.8586-8599.2004.

Abstract

Integrin-mediated adhesion of epithelial cells to extracellular matrix (ECM) proteins induces prolonged tyrosine phosphorylation and partial activation of epidermal growth factor receptor (EGFR) in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase Cgamma, and activation of the Ras/Erk and phosphatidylinositol 3'-kinase/Akt signaling pathways. In contrast, activation of focal adhesion kinase, Src, and protein kinase C, adhesion to matrix proteins, cell spreading, migration, and actin cytoskeletal rearrangements are induced independently of EGFR kinase activity. The ability of integrins to induce the activation of EGFR and its subsequent regulation of Erk and Akt activation permitted adhesion-dependent induction of cyclin D1 and p21, Rb phosphorylation, and activation of cdk4 in epithelial cells in the absence of exogenous growth factors. Adhesion of epithelial cells to the ECM failed to efficiently induce degradation of p27, to induce cdk2 activity, or to induce Myc and cyclin A synthesis; subsequently, cells did not progress into S phase. Treatment of ECM-adherent cells with EGF, or overexpression of EGFR or Myc, resulted in restoration of late-G(1) cell cycle events and progression into S phase. These results indicate that partial activation of EGFR by integrin receptors plays an important role in mediating events triggered by epithelial cell attachment to ECM; EGFR is necessary for activation of multiple integrin-induced signaling enzymes and sufficient for early events in G(1) cell cycle progression. Furthermore, these findings suggest that EGFR or Myc overexpression may provoke ligand-independent proliferation in matrix-attached cells in vivo and could contribute to carcinoma development.

摘要

整合素介导上皮细胞与细胞外基质(ECM)蛋白的黏附,以整合素依赖性且表皮生长因子受体(EGFR)配体非依赖性的方式诱导酪氨酸的持续磷酸化以及EGFR的部分激活。上皮细胞中整合素介导的EGFR激活对于先前已证明由细胞黏附于基质蛋白所诱导的多个信号转导事件是必需的,这些事件包括Shc、Cbl和磷脂酶Cγ的酪氨酸磷酸化,以及Ras/Erk和磷脂酰肌醇3'-激酶/Akt信号通路的激活。相比之下,黏着斑激酶、Src和蛋白激酶C的激活、与基质蛋白的黏附、细胞铺展、迁移以及肌动蛋白细胞骨架重排是独立于EGFR激酶活性而被诱导的。在没有外源性生长因子的情况下,整合素诱导EGFR激活及其随后对Erk和Akt激活的调节能力使得上皮细胞中细胞周期蛋白D1和p21的黏附依赖性诱导、Rb磷酸化以及cdk4激活成为可能。上皮细胞与ECM的黏附未能有效诱导p27的降解、诱导cdk2活性或诱导Myc和细胞周期蛋白A的合成;随后,细胞无法进入S期。用表皮生长因子处理黏附于ECM的细胞,或过表达EGFR或Myc,导致G1期晚期细胞周期事件的恢复并进入S期。这些结果表明,整合素受体对EGFR的部分激活在介导上皮细胞附着于ECM引发的事件中起重要作用;EGFR对于多种整合素诱导的信号酶的激活是必需的,并且对于G1期细胞周期进程中的早期事件是足够的。此外,这些发现表明,EGFR或Myc的过表达可能在体内引发基质附着细胞中不依赖配体的增殖,并可能促进癌症发展。

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