Kinases involved in MSP/RON signaling

Macrophage stimulating protein (MSP) belongs to the plasminogen-related kri ngle domain family. In addition to stimulation of macrophages, MSP acts on other cell types including epithelial and hematopoietic cells. The MSP rece ptor is a transmembrane tyrosine kinase called RON in humans and STK in mic e. MSP/receptor interaction induces activation of signal transduction pathw ays that mediate MSP biological activities, Cytoplasmic kinases are intrace llular messengers occupying an important role in signal transduction. We ha ve identified kinases that participate in RON signaling. In addition to pre viously identified involvement of phosphatidylinositol 3-kinase (PI3-K), JN K, and MAPK, we found that FAK, c-Src, and AKT are rapidly and transiently activated by MSP, FAK, MAPK, and c-Src are involved in MSP-induced cell pro liferation. MAPK and c-Src are components of one signal transduction cascad e, and MAPK is downstream of c-Src, FAK also regulates MSP-induced cell gro wth, but via a path different from c-Src/MAPK. AKT kinase is a component of a separate branch of the RON/PI3-K pathway that mediates the MSP anti-apop totic effect on epithelial cells, PIS-IC regulates MSP-induced adhesion and motility but via downstream components different from AKT. Thus, occupancy of the RON receptor by MSP activates distinct signal transduction pathways that mediate several cellular responses.