Characterization of the signaling capacities of the novel gp130-like cytokine receptor.
The gp130-like receptor (GPL) is a recently cloned member of the family of type I cytokine receptors. The name reflects its close relationship to gp130, the common receptor subunit of the interleukin (IL)-6-type cytokines. Indeed, the recently proposed ligand for GPL, IL-31, is closely related to the IL-6-type cytokines oncostatin M, leukemia inhibitory factor, and cardiotrophin-1. The second signal transducing receptor for IL-31 seems to be the oncostatin M receptor beta (OSMRbeta). The present study characterizes in depth the molecular mechanisms underlying GPL-mediated signal transduction. GPL is a strong activator of STAT3 and STAT5, whereas STAT1 is only marginally tyrosine-phosphorylated. We identify tyrosine residues 652 and 721 in the cytoplasmic region of the longest isoform of GPL (GPL(745)) as the major STAT5- and STAT3-activating sites, respectively. Additionally, we demonstrate Jak1 binding to GPL and its activation in heteromeric complexes with the OSMRbeta but also in a homomeric receptor complex. Most interesting, unlike OSMRbeta and gp130, GPL is insufficient to mediate ERK1/2 phosphorylation. We propose that this is due to a lack of recruitment of the tyrosine phosphatase SHP-2 or the adaptor protein Shc to the cytoplasmic domain of GPL.
Dreuw
Alexandra
A
Institut für Biochemie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Radtke
Simone
S
Pflanz
Stefan
S
Lippok
Barbara E
BE
Heinrich
Peter C
PC
Hermanns
Heike M
HM
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D053677:Receptors, Oncostatin M; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D007378:Interleukins; D008894:Milk Proteins; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C456339:cytokine receptor, GLM-R