Semaphorins Signal a New Pathway

Abstract

Giordano et al. have discovered a novel biological function for the semaphorins, mediated through coupling of the semaphorin receptor Plexin B1 to a structurally related receptor tyrosine kinase encoded by the proto-oncogene met . The semaphorins, a large family of secreted and membrane-bound proteins, regulate axonal pathfinding and play a prominent role in nervous system development. The widespread distribution of semaphorin receptors in various adult and embryonic tissues, however, suggests that these proteins may serve nonneuronal functions as well. Giordano et al. found that Semaphorin 4D (Sema 4D) elicited a pattern of cell proliferation, migration, anchorage-independent growth, and branching morphology in a hepatic cell line. The response was identical to "invasive growth," a programmed cellular response to Scatter Factor 1 (SF-1, also known as hepatocyte growth factor) activation of the Met receptor, leading the authors to investigate the possible role of Met in the response to Sema 4D. Using Western analysis, the authors demonstrated that endogenous Plexin B1 and Met immunoprecipitated as a complex, as did proteins encoded by constructs containing the extracellular domains of both receptors. Sema 4D elicited tyrosine phosphorylation of Plexin B1, Met, and a Met substrate. Cells overexpressing Plexin B1 constitutively displayed the invasive phenotype and showed basal Met phosphorylation. The response to Sema 4D depended on expression of a functional Met receptor and was inhibited by a Met dominant-negative construct. These results expand the spectrum of known semaphorin functions, and raise the intriguing possibility that the semaphorins could be implicated in metastatic processes through activation of the Met pathway. S. Giordano, S. Corso, P. Conrotto, S. Artigiani, G. Gilestro, D. Barberis, L. Tamagnone, P. M. Comiglio, The Semaphorin 4D receptor controls invasive growth by coupling with Met. Nat. Cell Biol. 4 , 720-724 (2002). [Online Journal]