SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130.
Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3.
Schmitz
J
J
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrabetae 30, D-52074 Aachen, Germany.
Weissenbach
M
M
Haan
S
S
Heinrich
P C
PC
Schaper
F
F
D015703:Antigens, CD / Q000378:metabolism*; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D050822:Cytokine Receptor gp130; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000737:chemistry; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors / Q000235:genetics; D018909:src Homology Domains; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D002352:Carrier Proteins; D050822:Cytokine Receptor gp130; D005982:Glutathione Transferase; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014443:Tyrosine; D000511:alpha-Macroglobulins; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human