Beviglia L, Kramer R H
Department of Stomatology, University of California, San Francisco, San Francisco, CA, USA.
Int J Cancer. 1999 Nov 26;83(5):640-9. doi: 10.1002/(sici)1097-0215(19991126)83:5<640::aid-ijc13>3.0.co;2-d.
Expression of hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, is positively correlated with breast carcinoma progression. We found that in invasive and metastatic MTLn3 breast carcinoma cells, HGF stimulated both initial adhesion to and motility on the extracellular matrix (ECM) ligands laminin 1, type I collagen, and fibronectin. Next, analysis with function-perturbing antibodies showed that adhesion to the different ECM proteins was mediated through specific beta1 integrins. In MTLn3 cells, HGF induced rapid tyrosine phosphorylation and activation of both c-Met and focal adhesion kinase (FAK). Cell anchorage and adhesion to the ECM substrates was required for HGF-induced FAK activation, since HGF failed to trigger tyrosine phosphorylation of FAK in suspended cells. Our results provide evidence that the 2 signaling pathways, integrin/ECM and c-Met/HGF, cooperate synergistically to induce FAK activation in an adhesion-dependent manner, leading to enhanced cell adhesion and motility. Moreover, we found that a FRNK (the FAK-related non-kinase)-like molecule is expressed in MTLn3 cells. Since FRNK acts as a competitive inhibitor of FAK function, our results suggest that a FRNK-like protein could facilitate disassembly of focal adhesions and likely be responsible for the HGF-induced scattering and motility of MTLn3 cells.
肝细胞生长因子（HGF）及其酪氨酸激酶受体c-Met的表达与乳腺癌进展呈正相关。我们发现，在侵袭性和转移性MTLn3乳腺癌细胞中，HGF可刺激细胞对细胞外基质（ECM）配体层粘连蛋白1、I型胶原和纤连蛋白的初始黏附及迁移。接下来，使用功能阻断抗体进行分析表明，对不同ECM蛋白的黏附是通过特定的β1整合素介导的。在MTLn3细胞中，HGF可诱导c-Met和黏着斑激酶（FAK）快速发生酪氨酸磷酸化并激活。HGF诱导的FAK激活需要细胞锚定并黏附于ECM底物，因为HGF无法在悬浮细胞中触发FAK的酪氨酸磷酸化。我们的结果证明，整合素/ECM和c-Met/HGF这两条信号通路以黏附依赖的方式协同作用，诱导FAK激活，从而增强细胞黏附和迁移。此外，我们发现MTLn3细胞中表达一种FAK相关非激酶（FRNK）样分子。由于FRNK可作为FAK功能的竞争性抑制剂，我们的结果表明，一种FRNK样蛋白可能促进黏着斑的解体，并可能是MTLn3细胞HGF诱导的散射和迁移的原因。
