The tyrosine 974 within the LIF-R-chain of the gp130/LIF-R heteromeric receptor complex mediates negative regulation of LIF signalling.
Signalling of interleukin (IL)-6 and interleukin-11 through gp130 homodimeric receptor complexes has been analysed with respect to initiation and termination of signalling in great detail. Gp130 contains a crucial motif around tyrosine Y759, which mediates negative regulation through the feedback inhibitor SOCS3 and the protein tyrosine phosphatase SHP2. Signalling of leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), CT-1-like factor (CLC) or oncostatin M (OSM) through gp130/LIF-R is believed to be similar due to the presence of the common signal transducer gp130 within the receptor complexes utilized, but the difference in the composition of gp130/gp130-homodimers and gp130/LIF-R-heterodimers is likely to be reflected in different signalling. Here, we analysed the contribution of the LIF-R within the gp130/LIF-R complex to negative regulation mediated by SHP2 and SOCS3. We show that SHP2 contributes to the negative regulation of signalling through gp130/LIF-R complexes. The inhibitory tyrosine motifs within the cytoplasmic parts of gp130 and the LIF-R act independently. Whereas SHP2 and SOCS3 bind directly to the inhibitory motif of gp130, only SHP2 was found to bind to the corresponding inhibitory sequence of the LIF-R. This observation was further corroborated by experiments indicating that mainly gp130 contributes to the inhibition of signalling by SOCS3.
Clahsen
Thomas
T
Department of Biochemistry, Medical School RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Lehmann
Ute
U
Stross
Claudia
C
Hermanns
Heike M
HM
Volkmer-Engert
Rudolf
R
Schneider-Mergener
Jens
J
Heinrich
Peter C
PC
Schaper
Fred
F
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D050822:Cytokine Receptor gp130; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000378:metabolism; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D015703:Antigens, CD; C494199:IL6ST protein, human; D047908:Intracellular Signaling Peptides and Proteins; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008562:Membrane Glycoproteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D050822:Cytokine Receptor gp130; D014443:Tyrosine; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases