ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells
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DOI：
10.1242/jcs.050906
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发表时间：
2010-04-15
影响因子：
4
通讯作者：
Reginato, Mauricio J.
中科院分区：
文献类型：
--
作者：
Haenssen, Keneshia K.;Caldwell, Sarah A.;Reginato, Mauricio J.
ErbB 2是一种在许多肿瘤中高度表达的受体酪氨酸激酶，已知其抑制凋亡信号。ErbB 2的过表达导致抗失巢凋亡，这有助于体外三维乳腺上皮腺泡结构的管腔填充。鉴于整合素和生长因子受体在功能上高度相互依赖，我们研究了整合素亚基在ErbB 2介导的生存信号传导中的作用。在这里，我们表明，MCF-10A细胞过度表达ErbB 2上调整合素α 5通过三维腺泡中的MAP-激酶途径，并发现在人类乳腺癌中与ErbB 2状态相关的整合素α 5水平升高。整合素α 5是ErbB 2介导的失巢凋亡抗性和最佳ErbB 2信号传导至Mek-Erk-Bim轴所需的，因为整合素α 5的耗尽逆转失巢凋亡抗性和Bim抑制。整合素α 5是Y877上ErbB 2酪氨酸磷酸化的完全激活所必需的，并且ErbB 2磷酸化与在不存在粘附的情况下Src的活性增加相关。事实上，我们表明，在细胞脱离过程中阻断Src活性升高逆转ErbB 2介导的生存和Bim抑制。因此，整合素α 5作为Src和ErbB 2-生存信号在低粘附状态，这是必要的，以阻止促失巢凋亡介质Bim的关键介质，我们认为，这一途径代表了一个潜在的新的治疗靶点ErbB 2阳性肿瘤。
ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, we examined the role of integrin subunits in ErbB2-mediated survival signaling. Here, we show that MCF-10A cells overexpressing ErbB2 upregulate integrin alpha 5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin alpha 5 levels associated with ErbB2 status in human breast cancer. Integrin alpha 5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin alpha 5 reverses anoikis resistance and Bim inhibition. Integrin alpha 5 is required for full activation of ErbB2 tyrosine phosphorylation on Y877 and ErbB2 phosphorylation is associated with increased activity of Src in the absence of adhesion. Indeed, we show that blocking elevated Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, integrin alpha 5 serves as a key mediator of Src and ErbB2-survival signaling in low adhesion states, which are necessary to block the pro-anoikis mediator Bim, and we suggest that this pathway represents a potential novel therapeutic target in ErbB2-positive tumors.