Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism

Macrophage stimulating protein (MSP) is a growth and motility factor that m ediates its activity via the RON/STK receptor tyrosine kinase. MSP promotes integrin-dependent epithelial cell migration, which suggests that MSP may regulate integrin receptor functions. Integrins are cell surface receptors for extracellular matrix. Epithelial cell adhesion and motility are mediate d by integrins. We studied the enhancement by MSP of cell. adhesion and the molecular mechanisms mediating this effect. MSP decreased the time require d for adhesion of 293 and RE7 epithelial cells to substrates coated with co llagen or fibronectin. Prevention of adhesion by an RGD-containing peptide showed that the cell-substrate interaction was mediated by integrins. Wortm annin, an inhibitor of phosphatidylinositol 3-kinase (PIS-K), blocked MSP-d ependent adhesion, which shows that PI3-K is in the MSP-induced adhesion pa thway. MSP also affected focal adhesion kinase (FAR) which is important for some types of cell adhesion and motility. Although MSP caused PI3-K-indepe ndent tyrosine phosphorylation and activation of FAK, experiments with domi nant-negative FAK constructs showed that FAK does not mediate the effects o f MSP on cell adhesion or motility. Thus PIS-K, but not FAK, mediates MSP-i nduced integrin-dependent adhesion of epithelial cells. Also, we found liga nd-independent association between RON and beta 1 integrin, which is additi onal evidence for a relationship between these two receptor systems.