ONCOSTATIN-M STIMULATES TYROSINE PROTEIN-PHOSPHORYLATION IN PARALLEL WITH THE ACTIVATION OF P42(MAPK) ERK-2 IN KAPOSI CELLS - EVIDENCE THATTHIS PATHWAY IS IMPORTANT IN KAPOSI CELL-GROWTH/

Oncostatin-M (OSM) is a potent mitogen for Kaposi's sarcoma (KS) cells . We studied signaling by the OSM receptor in three AIDS-related KS li nes and show induction of tyrosine phosphorylation of 145-, 120-, 85-, and 42-kD substrates. The 42-kD substrate was identified as p42MAPK ( mitogen-activated protein kinase), also known as ERK-2. This serine/th reonine kinase relays mitogenic signals from receptor tyrosine protein kinases (TPKs) or receptor-associated TPKs to transcriptional activat ors. The OSM dose dependence for MAP kinase activation and induction o f KS cell growth were almost identical, suggesting functional linkage. MAP kinase activation was dependent on tyrosine phosphorylation, and both OSM-induced MAP kinase activity and KS cell growth could be suppr essed by TPK inhibitors, genistein and geldanomycin. OSM also stimulat ed tyrosine phosphorylation of similar substrates and MAP kinase activ ity in human vein endothelial cells. While it has been proposed that t he OSM receptor may include the gp130 subunit of the IL-6 receptor and alpha-chain of leukemia inhibitory factor (LIF) receptor, neither LIF nor r.IL-6 induced tyrosine protein phosphorylation or p42MAPK activa tion in KS cells. However, r.IL-6 did stimulate tyrosine phosphorylati on and p42MAPK activity in the human B cell line, AF-10, while OSM and LIF exerted no effects. Our results indicate that, although the OSM a nd IL-6 receptors share a common signaling pathway, this pathway is se lectively activated by OSM in Kaposi's cells.