Oncostatin M-induced activation of stress-activated MAP kinases depends on tyrosine 861 in the OSM receptor and requires Jak1 but not Src kinases.
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.
Böing
Irene
I
Institut für Biochemie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
Stross
Claudia
C
Radtke
Simone
S
Lippok
Barbara E
BE
Heinrich
Peter C
PC
Hermanns
Heike M
HM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D053613:Janus Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D053683:Oncostatin M; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000187:drug effects / Q000378:metabolism*; D053677:Receptors, Oncostatin M; D014443:Tyrosine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D016207:Cytokines; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D007093:Imidazoles; C508351:OSM protein, human; C508352:Osm protein, mouse; D011725:Pyridines; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole