Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
Oncogene. 2010 Apr 22;29(16):2368-80. doi: 10.1038/onc.2009.514. Epub 2010 Jan 25.
Matrix remodeling, degradation, inflammation and invasion liberate peptide fragments that can subsequently interact with cells in an attachment-independent manner. Such 'soluble' matrix components, including collagens, fibronectin and laminin, induced Smad activation (termed crosstalk signaling), which follows a similar chronological sequence and R-Smad specificity as induced by transforming growth factor (TGF)-beta1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-beta scavenging antibody affected only TGF-beta1, but not crosstalk-induced responses. TGF-beta type II receptor mutation (DR26Delta25), which is deficient in TGF-beta type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-beta signaling. Consequentially, TGF-beta ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin beta1 receptor as showed by RNA interference. Co-immunoprecipitation (co-IP) and fluorescent microscopy indicate the involvement of focal adhesion kinase (FAK) and Src activity in collagen-induced signal propagation, and suggest a membrane signaling complex formation that includes both TGF-beta receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-beta1, supporting its separate function. This signaling mechanism expands and partially explains TGF-beta receptor dynamics and consequential signaling diversity-related gene expressional plasticity.
基质重塑、降解、炎症和浸润会释放出肽片段，这些片段可以以不依赖于附着的方式与细胞相互作用。这种“可溶性”基质成分，包括胶原、纤维连接蛋白和层粘连蛋白，诱导 Smad 激活（称为串扰信号），其遵循与转化生长因子 (TGF)-β1 诱导相似的时间顺序和 R-Smad 特异性。胶原结合会导致 Smad4 核易位，表明下游信号传递。TGF-β 清除抗体仅影响 TGF-β1，而不影响串扰诱导的反应。TGF-β 型 II 受体突变（DR26Delta25），其缺乏 TGF-β 型 I 受体募集到配体，诱导异四聚体信号复合物，并仅通过胶原诱导而不是 TGF-β 信号传播 Smad2 激活。因此，串扰信号不需要 TGF-β 配体参与。这种信号需要功能性整合素 β1 受体，如 RNA 干扰所示。共免疫沉淀 (co-IP) 和荧光显微镜表明，粘着斑激酶 (FAK) 和Src 活性参与胶原诱导的信号传递，并且表明包括 TGF-β 受体和整合素在内的膜信号复合物的形成。相关基因表达反应与 TGF-β1 诱发的反应不同，支持其独立功能。这种信号机制扩展并部分解释了 TGF-β 受体动力学和随后的信号多样性相关基因表达可塑性。
