Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

Abstract

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 (Tyr 837 /Tyr 839 ) 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 (Phe 820 ) in the human receptor that is responsible for this preference. Exchange by the murine counterpart (Cys 815 ) 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 Tyr 917 /Tyr 945 of the OSMR are crucial for STAT3 activation.

Oncostatin M-Induced and Constitutive Activation of the JAK2/STAT5/CIS Pathway Suppresses CCL1, but Not CCL7 and CCL8, Chemokine Expression

“…4B, upper panel). Previous studies have shown that STAT5 can be directly activated by JAK2 after cytokine stimulation (30,32). To corroborate our results, we treated HDFs with AG490, an inhibitor with higher affinity to JAK2 than to other JAK family members.…”

“…Previous work has highlighted the importance of JAK2 for the STAT5 tyrosine phosphorylation (30,32).…”

“…Immediately after stimulation, cells were lysed in Triton lysis buffer as described previously (30). All steps of cell lysis were performed at 4°C using ice-cold buffers.…”

Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis

“…In a recent study, our group showed that JAK-2 significantly contributes to OSM-induced STAT-5 activation (44). Thus, the JAK-2 inhibitor AG490 was used to compare the impact of STAT-5 with the impact of MAPK on CCL13 expression in normal SFs.…”

Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3)

“…Indeed, tyrosine residues at positions 917 (Tyr-917) and 945 (Tyr-945) serve as docking sites for STAT3 in OSM signaling (21). To analyze the role of Tyr-917 and Tyr-945 in STAT3 activation by a receptor complex composed of OSMR␤ and IL-31R␣, we created single and double mutants of OSMR␤ in which the tyrosines were substituted by phenylalanine (Y917F, Y945F, and Y917F/Y945F).…”