Falcioni R, Antonini A, Nisticò P, Di Stefano S, Crescenzi M, Natali P G, Sacchi A
Laboratorio Oncogenesi Molecolare, Istituto Regina Elena, Centro Ricerca Sperimentale, Rome, Italy.
Exp Cell Res. 1997 Oct 10;236(1):76-85. doi: 10.1006/excr.1997.3695.
Growth factors modulate integrin-mediated cell adhesion and motility, and their receptors are thought to share proteins that mediate intracellular signaling with integrin receptors. The crosstalk between these receptors is thought to play a relevant role in transformation and tumor progression. To highlight possible interactions between growth factors and cell adhesion receptors we investigated whether integrins associate with tyrosine kinase receptors in tumor cells. By affinity chromatography and Western blot analyses of purified immune complexes, we studied the association of laminin receptors (alpha 6 beta 1 and alpha 6 beta 4) with ErbB-2 tyrosine kinase in human carcinoma cell lines. We demonstrated that the alpha 6 beta 4 and alpha 6 beta 1 integrins coprecipitated with ErbB-2 in lysates from carcinoma or NIH3T3 cells overexpressing ErbB-2. Integrin-mediated activation of ErbB-2 receptors suggested that this association is functionally meaningful. Indeed, carcinoma cells treated with a monoclonal antibody to the alpha 6 integrin subunit showed a ligand-dependent increase of ErbB-2-phosphorylated molecules coprecipitated with integrins and an increased DNA synthesis. The interaction between growth factor receptors and integrins was also studied in NIH3T3 cells overexpressing alpha 6 beta 4 receptors and ErbB-2 protein. We report that cells overexpressing both receptors, but not those overexpressing a crippled ErbB-2, showed enhanced proliferation rates and invasiveness, further suggesting that alpha 6 beta 4 integrin and ErbB-2 receptor interaction might contribute to generate a more malignant phenotype in carcinoma cells.
生长因子可调节整合素介导的细胞黏附和运动，并且人们认为其受体与整合素受体共享介导细胞内信号传导的蛋白质。这些受体之间的相互作用被认为在肿瘤转化和进展过程中发挥着重要作用。为了突出生长因子与细胞黏附受体之间可能存在的相互作用，我们研究了整合素是否与肿瘤细胞中的酪氨酸激酶受体相关联。通过对纯化免疫复合物的亲和层析和蛋白质印迹分析，我们研究了人癌细胞系中层粘连蛋白受体（α6β1和α6β4）与ErbB-2酪氨酸激酶的关联。我们证明，在过表达ErbB-2的癌细胞或NIH3T3细胞的裂解物中，α6β4和α6β1整合素与ErbB-2共沉淀。整合素介导的ErbB-2受体激活表明这种关联在功能上具有重要意义。实际上，用针对α6整合素亚基的单克隆抗体处理的癌细胞显示，与整合素共沉淀的ErbB-2磷酸化分子呈配体依赖性增加，并且DNA合成增加。我们还在过表达α6β4受体和ErbB-2蛋白的NIH3T3细胞中研究了生长因子受体与整合素之间的相互作用。我们报告称，过表达这两种受体的细胞，而非过表达缺陷型ErbB-2的细胞，显示出增殖率和侵袭性增强，这进一步表明α6β4整合素与ErbB-2受体的相互作用可能有助于在癌细胞中产生更恶性的表型。
