MACROPHAGE-STIMULATING PROTEIN INDUCES PROLIFERATION AND MIGRATION OFMURINE KERATINOCYTES

Macrophage stimulating protein (MSP) is a chemotactic factor for murin e peritoneal macrophages. The receptor for human MSP was recently iden tified as the ron gene product, a transmembrane protein tyrosine kinas e cloned from a human keratinocyte cDNA library. Here we report that M SP induced proliferation of murine primary keratinocytes and establish ed keratinocyte cell lines in a concentration-dependent manner. The gr owth efficacy of MSP was comparable to that of epidermal growth factor and keratinocyte growth factor. In three of four cell lines tested in a chemotaxis chamber, MSP also stimulated migration of keratinocytes on a collagen type IV substratum. The action of MSP was mediated by sp ecific binding of MSP to the STK gene product, a murine homologue of t he RON MSP receptor. Binding of MSP to keratinocyte STK induced phosph orylation of the 150 kDa STK beta chain. Herbimycin A, a protein tyros ine kinase inhibitor, blocked MSP-mediated phosphorylation of the STK receptor as well as proliferation of keratinocytes, suggesting the imp ortance of tyrosine kinase activity for transduction of the message de livered by MSP. Previously, the only known target cell for MSP was the resident peritoneal macrophage. These studies establish the keratinoc yte as a new target cell for MSP. The action of MSP on keratinocytes m ay have implications for tissue repair, wound healing, and tumor growt h. (C) 1996 Academic Press, Inc.