SHPS-1/SIRP1α contributes to interleukin-6 signalling

Abstract The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1α/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1α to IL-6 type cytokine signalling. SIRP1α binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1α protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1α affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1α-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1α 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.