Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor
Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor
复制标题
DOI：
10.1242/jcs.091652
复制
发表时间：
2012-01-15
影响因子：
4
通讯作者：
Faessler, Reinhard
中科院分区：
文献类型：
--
作者：
Azimifar, S. Babak;Boettcher, Ralph T.;Faessler, Reinhard
整合素和受体酪氨酸激酶信号网络协同调节各种生物功能。两种信号网络整合背后的分子细节在很大程度上仍然未知。在这里，我们确定了一个由纤连蛋白-α5β1-整合素-整合素连接激酶（ILK）复合物组成的信号模块，该复合物与表皮生长因子（EGF）信号相配合，协同控制成纤维细胞中基于肌动蛋白的瞬时圆形背侧皱褶（DR）的形成。 DR 的形成取决于整合素和 EGF 受体信号以 ILK 依赖性方式对粘着斑处 Src 的精确空间激活。在基于 SILAC 的磷酸蛋白质组学筛选中，我们鉴定出肿瘤抑制因子 Cyld 是 α5β1 整联蛋白和 EGF 受体协同信号传导诱导的 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，作为 DR 形成的先决条件。这项研究为整合素 ILK 和 EGF 信号串扰在介导 Cyld 酪氨酸磷酸化和基于快速肌动蛋白的细胞骨架重排中的新功能提供了证据。
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-alpha 5 beta 1-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 alpha 5 beta 1 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.