Box 2 region of the oncostatin M receptor determines specificity for recruitment of Janus kinases and STAT5 activation.
Human and murine oncostatin M (OSM) induce their bioactivities through a heterodimeric receptor complex consisting of gp130 and the OSM receptor (OSMR), which initiates a signaling pathway involving Janus kinases (JAKs) and transcription factors of the signal transducers and activators of transcription (STAT) family. In contrast to the signal transducing receptor subunit gp130, the OSMR allows strong activation of STAT5B. The underlying molecular mechanism, however, remained unclear. Here we demonstrate that the human and murine OSM receptors use distinct mechanisms for STAT5B activation. The human receptor contains a STAT5B recruiting tyrosine motif (Tyr837/Tyr839) C-terminal to the box 1/2 region, which is absent in the mouse receptor. In contrast, the murine receptor initiates STAT5 activation directly via the receptor bound Janus kinases. Intriguingly, the murine receptor preferentially recruits JAK2, whereas the human receptor seems to have a higher affinity for JAK1. We identify a single amino acid (Phe820) in the human receptor that is responsible for this preference. Exchange by the murine counterpart (Cys815) allows recruitment of JAK2 by the human receptor and consequently activation of STAT5B independently of receptor tyrosine motifs. STAT5B interacts directly with JAK2 only in response to activation of the murine OSMR or the mutated human OSMR. Additionally, we show that OSM-induced STAT1 phosphorylation occurs independently of receptor tyrosine motifs and is mediated directly by Janus kinases, whereas the two C-terminally located tyrosine residues Tyr917/Tyr945 of the OSMR are crucial for STAT3 activation.
Hintzen
Christoph
C
Institut für Biochemie, Universitätsklinikum RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Evers
Christina
C
Lippok
Barbara E
BE
Volkmer
Rudolf
R
Heinrich
Peter C
PC
Radtke
Simone
S
Hermanns
Heike M
HM
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053677:Receptors, Oncostatin M / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity
D053677:Receptors, Oncostatin M; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494096:Stat5b protein, mouse; D050822:Cytokine Receptor gp130; C507904:JAK1 protein, human; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2