Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
J Cell Sci. 2012 Jan 15;125(Pt 2):435-48. doi: 10.1242/jcs.091652.
Integrin and receptor tyrosine kinase signalling networks cooperate to regulate various biological functions. The molecular details underlying the integration of both signalling networks remain largely uncharacterized. Here we identify a signalling module composed of a fibronectin-α5β1-integrin-integrin-linked-kinase (ILK) complex that, in concert with epidermal growth factor (EGF) cues, cooperatively controls the formation of transient actin-based circular dorsal ruffles (DRs) in fibroblasts. DR formation depends on the precise spatial activation of Src at focal adhesions by integrin and EGF receptor signals, in an ILK-dependent manner. In a SILAC-based phosphoproteomics screen we identified the tumour-suppressor Cyld as being required for DR formation induced by α5β1 integrin and EGF receptor co-signalling. Furthermore, EGF-induced Cyld tyrosine phosphorylation is controlled by integrin-ILK and Src as a prerequisite for DR formation. This study provides evidence for a novel function of integrin-ILK and EGF signalling crosstalk in mediating Cyld tyrosine phosphorylation and fast actin-based cytoskeletal rearrangements.
整合素和受体酪氨酸激酶信号网络协同调节各种生物学功能。这两种信号网络整合的分子细节在很大程度上仍未被描述。在这里，我们鉴定了一个由纤维连接蛋白-α5β1-整合素-整合素连接激酶（ILK）复合物组成的信号模块，该模块与表皮生长因子（EGF）信号协同作用，共同控制成纤维细胞中瞬时基于肌动蛋白的背侧皱襞（DR）的形成。DR 的形成取决于整合素和表皮生长因子受体信号以 ILK 依赖的方式在粘着斑处精确地空间激活Src。在基于 SILAC 的磷酸化蛋白质组学筛选中，我们发现肿瘤抑制因子 Cyld 是由α5β1 整合素和表皮生长因子受体共信号诱导的 DR 形成所必需的。此外，EGF 诱导的 Cyld 酪氨酸磷酸化受整合素-ILK 和 Src 控制，是 DR 形成的前提。这项研究为整合素-ILK 和 EGF 信号转导在介导 Cyld 酪氨酸磷酸化和快速基于肌动蛋白的细胞骨架重排中的新功能提供了证据。
