Scatter Factor Receptors are Key Players in a Unique Multistep Program Leading to Invasive Growth

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Abstract
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.

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