SHPS-1/SIRP1alpha contributes to interleukin-6 signalling.
The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1alpha to IL-6 type cytokine signalling. SIRP1alpha binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1alpha protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1alpha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1alpha contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.
Sobota
Radoslaw M
RM
Department of Biochemistry, RWTH Aachen University, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Müller
Pia J
PJ
Khouri
Christina
C
Ullrich
Axel
A
Poli
Valeria
V
Noguchi
Tetsuya
T
Heinrich
Peter C
PC
Schaper
Fred
F
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D015533:Transcriptional Activation
D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D019000:Phosphotyrosine; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse