Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells

During the early stage (at 4 weeks) of interleukin-3 (IL-3)-induced development, mouse bone marrow-derived mast cells (BMMC) express alpha 4, alpha 5 and alpha 6 integrins, whereas with further maturation beyond 10 weeks, only alpha 5 integrin remains stably expressed. Hepatocyte growth factor (HGF) modulates the growth and movement of diverse cell types upon binding to its receptor, encoded by the proto-oncogene c-met. We report here the expression of c-mer by BMMC throughout the course of their development. In addition, HGF stimulated migration of early week-4 BMMC, but not of the later stage week-10 BMMC, on fibronectin and laminin substrates. The developmental stage-dependent effect of HGF on BMMC was due to specific stimulation of the migratory function of alpha 4 and alpha 6, but not alpha 5 integrins. In addition, HGF had no effect on BMMC growth, either alone or in combination with IL-3. While HGF is stimulatory of the migratory function of BMMC, our results show that BMMC in turn can modulate HGF function. Thus, upon activation via the IgE receptors, BMMC released proteases that abolished HGF activities. Analyses of the degradation products by two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot using antisera prepared against recombinant HGF and the kringle 3 domain of HGF revealed specific degradation of HGF alpha but not beta/beta' subunits. Therefore, our results suggest that: 1) the motogenic effect of HGF on BMMC varies according to the stage of their development, 2) HGF stimulation of BMMC migration is due to selective activation of alpha 4 and alpha 6, but not alpha 5 integrin function, and 3) there exists a two-way relationship between BMMC and HGF such that HGF stimulates the beta 1 integrin-mediated migratory function of BMMC, which can, in turn, modulate HGF function by release of serine proteases.