Oncostatin M induces tyrosine phosphorylation in endothelial cells and activation of p62yes tyrosine kinase.
Oncostatin M is a polypeptide cytokine produced by activated and transformed T lymphocytes that has diverse biologic effects, including growth inhibition of tumor cells and induction of IL-6 expression in cultured human endothelial cells (HEC). HEC are highly responsive to oncostatin M and express high levels of oncostatin M receptors relative to other cell types. Oncostatin M has previously been found to bind a specific receptor of 150 to 160 kDa. We have found through the use of anti-phosphotyrosine immunoblotting that oncostatin M induces tyrosine phosphorylation in HEC. Anti-phosphotyrosine antibodies specifically immunoprecipitated labeled oncostatin M cross-linked to its receptor, demonstrating that the oncostatin M receptor is either directly phosphorylated on tyrosine after ligand binding or is tightly associated with a phosphotyrosyl protein in these cells. The tyrosine kinase inhibitor herbimycin A blocked the induction of IL-6 by oncostatin M in HEC. In addition, immune complex kinase assays showed that oncostatin M markedly increased the activity of the p62yes tyrosine kinase with a small increase in p59fyn but no increase in p56lyn tyrosine kinase activity in HEC. We conclude that oncostatin M utilizes a tyrosine phosphorylation signal transduction pathway in HEC involving the activation of the p62yes tyrosine kinase, and that this tyrosine phosphorylation pathway leads to the induction of IL-6 expression.
Schieven
G L
GL
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Kallestad
J C
JC
Brown
T J
TJ
Ledbetter
J A
JA
Linsley
P S
PS
D016227:Benzoquinones; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D019833:Genistein; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D051575:Proto-Oncogene Proteins c-yes; D011809:Quinones / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000032:analysis; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D017828:Rifabutin / Q000031:analogs & derivatives; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases
D016227:Benzoquinones; D016207:Cytokines; D015850:Interleukin-6; D007529:Isoflavones; D047029:Lactams, Macrocyclic; C508351:OSM protein, human; D010455:Peptides; D011518:Proto-Oncogene Proteins; D011809:Quinones; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051575:Proto-Oncogene Proteins c-yes; D019061:src-Family Kinases