Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this 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 lines 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/threonine kinase relays mitogenic signals from receptor tyrosine protein kinases (TPKs) or receptor-associated TPKs to transcriptional activators. The OSM dose dependence for MAP kinase activation and induction of 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 suppressed by TPK inhibitors, genistein and geldanomycin. OSM also stimulated tyrosine phosphorylation of similar substrates and MAP kinase activity in human vein endothelial cells. While it has been proposed that the 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 activation in KS cells. However, r.IL-6 did stimulate tyrosine phosphorylation 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 and IL-6 receptors share a common signaling pathway, this pathway is selectively activated by OSM in Kaposi's cells.
Amaral
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MC
Department of Medicine, UCLA School of Medicine 90024-1680.
Miles
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Kumar
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Nel
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D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D016227:Benzoquinones; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic; D019950:Mitogen-Activated Protein Kinase 1; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000473:pathology*; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014471:Umbilical Veins
D016227:Benzoquinones; D006131:Growth Inhibitors; D047029:Lactams, Macrocyclic; C508351:OSM protein, human; D010455:Peptides; D010750:Phosphoproteins; D011809:Quinones; D053683:Oncostatin M; D019000:Phosphotyrosine; D014443:Tyrosine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D013936:Thymidine; C001277:geldanamycin