Shakibaei M, John T, De Souza P, Rahmanzadeh R, Merker H J
Institute of Anatomy, Free University Berlin, Königin-Luise-Strasse 15, D-14195 Berlin, Germany.
Biochem J. 1999 Sep 15;342 Pt 3(Pt 3):615-23.
We have examined the mechanism by which collagen-binding integrins co-operate with insulin-like growth factor-I (IGF-I) receptors (IGF-IR) to regulate chondrocyte phenotype and differentiation. Adhesion of chondrocytes to anti-beta1 integrin antibodies or collagen type II leads to phosphorylation of cytoskeletal and signalling proteins localized at focal adhesions, including alpha-actinin, vinculin, paxillin and focal adhesion kinase (FAK). These stimulate docking proteins such as Shc (Src-homology collagen). Moreover, exposure of collagen type II-cultured chondrocytes to IGF-I leads to co-immunoprecipitation of Shc protein with the IGF-IR and with beta1, alpha1 and alpha5 integrins, but not with alpha3 integrin. Shc then associates with growth factor receptor-bound protein 2 (Grb2), an adaptor protein and extracellular signal-regulated kinase. The expression of the docking protein Shc occurs only when chondrocytes are bound to collagen type II or integrin antibodies and increases when IGF-I is added, suggesting a collaboration between integrins and growth factors in a common/shared biochemical signalling pathway. Furthermore, these results indicate that focal adhesion assembly may facilitate signalling via Shc, a potential common target for signal integration between integrin and growth-factor signalling regulatory pathways. Thus, the collagen-binding integrins and IGF-IR co-operate to regulate focal adhesion components and these signalling pathways have common targets (Shc-Grb2 complex) in subcellular compartments, thereby linking to the Ras-mitogen-activated protein kinase signalling pathway. These events may play a role during chondrocyte differentiation.
我们研究了胶原结合整合素与胰岛素样生长因子-I（IGF-I）受体（IGF-IR）协同调节软骨细胞表型和分化的机制。软骨细胞与抗β1整合素抗体或II型胶原的黏附导致定位于黏着斑的细胞骨架和信号蛋白磷酸化，包括α-辅肌动蛋白、纽蛋白、桩蛋白和黏着斑激酶（FAK）。这些刺激对接蛋白，如Shc（Src同源胶原）。此外，将II型胶原培养的软骨细胞暴露于IGF-I会导致Shc蛋白与IGF-IR以及β1、α1和α5整合素共免疫沉淀，但不与α3整合素共免疫沉淀。然后，Shc与生长因子受体结合蛋白2（Grb2）结合，Grb2是一种衔接蛋白和细胞外信号调节激酶。对接蛋白Shc仅在软骨细胞与II型胶原或整合素抗体结合时表达，并在添加IGF-I时增加，这表明整合素和生长因子在共同的生化信号通路中存在协作。此外，这些结果表明黏着斑组装可能促进通过Shc的信号传导，Shc是整合素和生长因子信号调节通路之间信号整合的潜在共同靶点。因此，胶原结合整合素和IGF-IR协同调节黏着斑成分，这些信号通路在亚细胞区室中有共同靶点（Shc-Grb2复合物），从而与Ras-丝裂原活化蛋白激酶信号通路相连。这些事件可能在软骨细胞分化过程中发挥作用。
