Integrins mediate cell adhesion by connecting the extracellular matrix to the intracellular cytoskeleton and orchestrate signal transduction in response to chemical and mechanical stimuli by interacting with many cytoplasmic proteins. We used BioID to interrogate the interactomes of β1 and β3 integrins in epithelial cells and identified PEAK1 as an interactor of the RGD-binding integrins α5β1, αVβ3, and αVβ5 in focal adhesions. We demonstrate that the interaction between integrins and PEAK1 occurs indirectly through Tensin3, requiring both the membrane-proximal NPxY motif on the integrin β tail and binding of the SH2 domain of Tensin3 to phosphorylated Tyr-635 on PEAK1. Phosphorylation of Tyr-635 is mediated by Src and regulates cell migration. Additionally, we found that Shc1 localizes in focal adhesions in a PEAK1 phosphorylated Tyr-1188–dependent fashion. Besides binding Shc1, PEAK1 also associates with a protein cluster that mediates late EGFR/Shc1 signaling. We propose a model in which PEAK1 binds Tensin3 and Shc1 to converge integrin and growth factor receptor signal transduction.

中文翻译：

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PEAK1 Y635 磷酸化通过与 Tensin3 和整合素结合调节细胞迁移

整合素通过将细胞外基质连接到细胞内细胞骨架来介导细胞粘附，并通过与许多细胞质蛋白相互作用来协调信号转导以响应化学和机械刺激。我们使用 BioID 来研究上皮细胞中 β1 和 β3 整合素的相互作用组，并确定 PEAK1 是粘着斑中 RGD 结合整合素 α5β1、αVβ3 和 αVβ5 的相互作用因子。我们证明整合素和 PEAK1 之间的相互作用通过 Tensin3 间接发生，需要整合素 β 尾部的近膜 NPxY 基序以及 Tensin3 的 SH2 结构域与 PEAK1 上磷酸化的 Tyr-635 的结合。 Tyr-635 的磷酸化由 Src 介导并调节细胞迁移。此外，我们发现 Shc1 以 PEAK1 磷酸化 Tyr-1188 依赖性方式定位于粘着斑。除了结合 Shc1 之外，PEAK1 还与介导晚期 EGFR/Shc1 信号传导的蛋白质簇相关。我们提出了一个模型，其中 PEAK1 结合 Tensin3 和 Shc1 以聚合整合素和生长因子受体信号转导。