Distinct functions of receptor-like tyrosine phosphatases CD45 and CD148 in chemoattractant-mediated neutrophil migration and response to S. aureus infection

摘要

Neutrophils, critical innate immune effectors, use bacterial-derived chemoattractant-induced G-protein coupled receptor (GPCR) signaling for their pursuit of bacteria. Tyrosine phosphorylation pathways and receptor-like tyrosine phosphatases (RPTPs) are rarely considered in chemoattractant-mediated GPCR signaling. Here, we report that two RPTPs CD45 and CD148, previously shown to share redundant roles in positively regulating Src Family Kinases (SFKs) in immunoreceptor signaling pathways in B cells and macrophages, are critical in the neutrophil response to S. aureus infection and, surprisingly, in chemoattractant-mediated chemotaxis. Remarkably, deficiency in either of these RPTPs influenced neutrophil GPCR responses in unique ways. Our results reveal that CD45 positively while CD148 positively and negatively regulate GPCR function and proximal signals including Ca²⁺, phosphatidylinositol 3′OH kinase (PI(3)K) and phosopho-extracellular regulated kinase (pERK) activity. Moreover, our results suggest that CD45 and CD148 preferentially target different SFK members Hck and Fgr vs Lyn, respectively, to positively and negatively regulate GPCR pathways.