Oncostatin M-induced activation of stress-activated MAP kinases depends on tyrosine 861 in the OSM receptor and requires Jak1 but not Src kinases

Abstract

We have investigated the molecular mechanisms involved in the activation process of the stress-activated protein kinases (SAPK) p38 and JNK in response to the interleukin-6-type cytokine oncostatin M (OSM). Interestingly, activation of p38 and JNK originates from tyrosine residue 861 in the OSMR; the same tyrosine residue which we identified before to be involved in the activation of the mitogen-activated kinases Erk1/2 [Hermanns, H. M., Radtke, S., Schaper, F., Heinrich, P. C., and Behrmann, I. (2000) J. Biol. Chem. 275, 40742–40748]. Therefore, activation of members belonging to all three MAPK families is mediated by one tyrosine motif in the cytoplasmic region of the human OSMR. Concomitantly, point mutation of this residue abrogates the phosphorylation of these kinases. The Janus kinase Jak1 is absolutely essential for the activation of p38 in response to OSM, while Src kinase family members appear to be generally dispensable. Finally, we demonstrate that mutation of tyrosine 861 abrogates OSMR-mediated cell proliferation and identify Erk1/2 as mainly responsible for the proliferative effect. Erk1/2 activation is negatively influenced by p38 activation and inhibition of p38 significantly prolongs the half-life of OSM-induced Egr-1.