Interactions between scatter factors and their receptors: hints for therapeutic applications

Abstract

The scatter factors, which include hepatocyte growth factor and macrophage stimulating protein, stand out from other cytokines because of their uncommon biological properties. In addition to promoting cell growth and protection from apoptosis, they are involved in the control of cell dissociation, migration into extracellular matrices, and a unique process of differentiation called 'branching morphogenesis'. Through the concerted regulation of these complex phenomena, scatter factors promote development, regeneration, and reconstruction of normal organ architecture. In transformed epithelia, scatter factors can mediate tumor invasive growth, a harmful feature of neoplastic progression in which cancer cells invade surrounding tissues, penetrate across the vascular walls, and eventually disseminate throughout the body, giving rise to systemic metastases. A much-debated issue in basic biology, which has strong implications for experimental medicine, is how to dissociate the favorable effects of growth factors from their adverse ones. Accordingly, to find agonists or antagonists with potential therapeutic applications is a crucial undertaking for current research. Domain-mapping analyses of growth factor molecules can help to isolate specific structural requirements for the induction of selective biological effects. Based on the observation that certain growth factors must undergo posttranslational modifications to exert a full response, it is possible to interfere with their activation mechanisms to modulate their functions. Finally, the identification of cell type-specific coreceptors able to potentiate their activity allows drawing of a functional body map, where some organs or tissues may be more responsive than others to growth factors. This review is focused on how, and to what extent, scatter factors can behave 'well' or 'badly' according to their molecular structure, the way they are activated, and the way they interact with cell surface receptors and coreceptors.

Expression and functional role of hepatocyte growth factor and its receptor (c-met) during fetal mouse testis development

“…As well demonstrated, HGF is a pleiotropic cytokine able to induce multiple biological activities in different cell types (Matsumoto & Nakamura 1993, Zarnegar & Michalopoulos 1995, Trusolino et al 1998, playing different roles during embryonic development and mediating essential interactions between mesenchymal and epithelial cells (Birchmeier & Gherardi 1998). The ability of HGF in inducing the morphogenesis of different epithelial cells, such as mammary gland and prostate cells, is also well documented (Brinkmann et al 1995).…”

Impairment of the antifibrotic effect of hepatocyte growth factor in lung fibroblasts from African Americans: Possible role in systemic sclerosis

“…In addition to c-Met, HGF also binds heparin and heparan sulfate proteoglycans on cell surfaces, albeit with 10-fold lower affinity (38,39). The proteoglycans do not transmit signals themselves, but rather, are thought to be required for the signaling receptor to generate a biologic response (40).…”

Hepatocyte Growth Factor Enhances Vascular Endothelial Growth Factor-Induced Angiogenesis in Vitro and in Vivo

“…11 Activation of c-met is known to stimulate phosphatidylinositol-3-kinase, phospholipase C␥, pp60 src , and Grb2/Sos1; signaling pathways also activated by VEGF. 37 However, the observed synergistic interactions between VEGF and HGF suggest that there may be differences in the signal transduction pathways. For example, induction of epithelial tubules by HGF is dependent on the STAT pathway.…”