Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition.
Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition.
复制标题
DOI：
10.1083/jcb.201508080
复制
发表时间：
2016-02-01
期刊：
影响因子：
--
通讯作者：
Humphries MJ
中科院分区：
文献类型：
--
作者：
Horton ER;Humphries JD;Stutchbury B;Jacquemet G;Ballestrem C;Barry ST;Humphries MJ
整合素粘附复合物（IAC）的粘附信号传导对关键IAC激酶（FAK和/或Src）的抑制敏感，但IAC组成不敏感，表明IAC组分的信号传导和结构贡献之间存在分离。整合素粘附复合物（IAC）在细胞外基质和肌动蛋白细胞骨架之间形成机械化学连接，并通过翻译后修饰介导表型反应。在这里，我们研究了IAC网络对关键IAC信号成分粘着斑激酶（FAK）和Src的药理学干扰的模块化和鲁棒性。使用AZ 13256675的FAK抑制阻断FAKY 397磷酸化，但不改变IAC组成，如质谱法所报告。IAC组合物也对单独使用AZD 0530或与FAK抑制组合使用的Src抑制不敏感。相反，激酶抑制实质上减少了IAC内的磷酸化、细胞迁移和增殖。此外，使用光漂白后的荧光恢复，我们发现FAK抑制增加了磷酸酪氨酸（pY）报告（dSH 2）在IAC的交换率。这些数据表明，通过IAC的激酶依赖性信号传播是独立的IAC组成的总体变化。总之，这些发现证明了IAC的组成与其传递pY依赖性信号的能力之间的一般分离。
Adhesion signaling of integrin adhesion complexes (IACs) is sensitive to inhibition of key IAC kinases (FAK and/or Src), but IAC composition is not, demonstrating a separation between signaling and structural contributions of IAC components. Integrin adhesion complexes (IACs) form mechanochemical connections between the extracellular matrix and actin cytoskeleton and mediate phenotypic responses via posttranslational modifications. Here, we investigate the modularity and robustness of the IAC network to pharmacological perturbation of the key IAC signaling components focal adhesion kinase (FAK) and Src. FAK inhibition using AZ13256675 blocked FAKY397 phosphorylation but did not alter IAC composition, as reported by mass spectrometry. IAC composition was also insensitive to Src inhibition using AZD0530 alone or in combination with FAK inhibition. In contrast, kinase inhibition substantially reduced phosphorylation within IACs, cell migration and proliferation. Furthermore using fluorescence recovery after photobleaching, we found that FAK inhibition increased the exchange rate of a phosphotyrosine (pY) reporter (dSH2) at IACs. These data demonstrate that kinase-dependent signal propagation through IACs is independent of gross changes in IAC composition. Together, these findings demonstrate a general separation between the composition of IACs and their ability to relay pY-dependent signals.