ACTIVATION OF MAP KINASES, PP90(RSK) AND PP70-S6 KINASES IN MOUSE MAST-CELLS BY SIGNALING THROUGH THE C-KIT RECEPTOR TYROSINE KINASE OR FC(EPSILON)RI - RAPAMYCIN INHIBITS ACTIVATION OF PP70-S6 KINASE AND PROLIFERATION IN MOUSE MAST-CELLS

The high-affinity receptor for IgE, Fc(epsilon)RI, represents the majo r cell surface structure through which mast cells express immunologica lly specific secretory function. By contrast, the stem cell factor rec eptor (SCFR), which is encoded by c-kit, is essential for normal mast cell development. The signaling pathways initiated by the stimulation of mast cells through the Fc(epsilon)RI, which lacks intrinsic kinase activity, and the SCFR, a member of the receptor tyrosine kinase famil y, generally have been regarded to be distinct. We report here that mo use mast cells stimulated either with SCF or with IgE and specific ant igen exhibit a remarkably similar pattern of activation of mitogen-act ivated protein kinases (MAPK), 90 kDa-S6 kinases (pp90rsk), and pp70-S 6 kinases (pp70-S6K). These results indicate that all three families o f protein kinases are associated with the cell surface receptor-depend ent activation of secretion, as well as proliferation, in mast cells.W e also show that the immunosuppressant rapamycin, but not FK506, can i nhibit both SCF-dependent pp70-S6 kinase activation and SCF-dependent proliferation in mouse mast cells, without suppressing IgE- and antige n-dependent mediator release. These findings suggest that the activati on of pp70-S6 kinase represents an important link in the stimulation o f cell proliferation by SCF. Our results also indicate that the intrac ellular signaling pathways initiated by stimulation of mast cells thro ugh the Fc(epsilon)RI or the SCFR exhibit more overlap than has previo usly been appreciated.