Bardelli A, Comoglio P M
Institute for Cancer Research (IRCC), University of Torino Medical School, Italy.
Ciba Found Symp. 1997;212:133-44; discussion 144-7. doi: 10.1002/9780470515457.ch9.
Hepatocyte growth factor/scatter factor (HGF/SF) is the prototype of a family of structurally related soluble molecules (scatter factors) which also includes the HGF-like/macrophage-stimulating protein (HGF1/MSP). HGF/SF and HGF1/MSP control a complex genetic program known as 'invasive growth' which leads to cell dissociation, proliferation, invasion of extracellular matrix, prevention of apoptosis, acquisition of polarity and tubule formation. The HGF/SF and HGF1/MSP receptors are the tyrosine kinases encoded by the homologous genes met and ron. During development coordinated control of invasive growth by HGF-Met is essential. Met and Ron receptor signalling occurs via a two-phosphotyrosine multifunctional docking site located in their C-terminal regions. Activation of Ras and phosphatidylinositol-3-kinase through the multifunctional docking site is required for receptor-mediated invasive growth. In a number of malignant tumours met and ron are mutated, amplified or overexpressed. Oncogenically activated met and ron confer transforming, invasive and metastatic properties to normal cells. Point mutations of the multifunctional docking site dissociate the transforming potential from the invasive-metastatic phenotype showing that distinct signalling pathways are involved. This review summarizes the recent progress made in understanding the signalling mechanisms initiated by the scatter factor receptors leading to invasive growth.
肝细胞生长因子/分散因子(HGF/SF)是一类结构相关的可溶性分子(分散因子)家族的原型,该家族还包括HGF样/巨噬细胞刺激蛋白(HGF1/MSP)。HGF/SF和HGF1/MSP控制着一种称为“侵袭性生长”的复杂遗传程序,这种程序会导致细胞解离、增殖、侵袭细胞外基质、防止细胞凋亡、获得极性以及形成小管。HGF/SF和HGF1/MSP的受体是由同源基因met和ron编码的酪氨酸激酶。在发育过程中,HGF-Met对侵袭性生长的协调控制至关重要。Met和Ron受体信号通过位于其C末端区域的双磷酸酪氨酸多功能对接位点发生。通过多功能对接位点激活Ras和磷脂酰肌醇-3-激酶是受体介导的侵袭性生长所必需的。在许多恶性肿瘤中,met和ron发生突变、扩增或过表达。致癌激活的met和ron赋予正常细胞转化、侵袭和转移特性。多功能对接位点的点突变使转化潜能与侵袭性转移表型分离,表明涉及不同的信号通路。本综述总结了在理解由分散因子受体引发的导致侵袭性生长的信号机制方面取得的最新进展。