Phosphatases Fight over fMLF

Science Signaling  13 Dec 2011:
Vol. 4, Issue 203, pp. ec348
DOI: 10.1126/scisignal.4203ec348

The migration of neutrophils to sites of bacterial infection along a gradient of bacterial-derived chemoattractants is critical for clearance of the infection. Chemoattractants, such as formyl-Met-Leu-Phe (fMLF), stimulate neutrophil G protein–coupled receptors (GPCRs), which trigger phosphoinositide 3-kinase (PI3K)–dependent signaling pathways that result in chemotaxis and the respiratory burst, which produces reactive oxygen species and is required to kill bacteria. Members of the Src family kinases (SFKs), such as Lyn, Fgr, and Hck, are required for some fMLF-dependent processes. Zhu et al. investigated roles for the membrane-bound, receptor-like protein tyrosine phosphatases (RPTPs) CD45 and CD148, which are implicated in SFK regulation, in mouse neutrophil responses to infection by Staphylococcus aureus. They found that mice deficient in CD45 (Ptprc–/– mice) had fewer neutrophils recruited to the site of infection and were less efficient at eliminating bacteria than were wild-type mice, whereas mice with nonfunctional CD148 (PtprjTM–/TM– mice) showed increased numbers of neutrophils and improved bacterial killing. No differences in neutrophil adhesion, phagocytosis, or respiratory burst were observed among the different strains. Instead, chemotactic responses and PI3K activity of Ptprc–/– neutrophils in response to fMLF were decreased compared with those of PtprjTM–/TM– neutrophils. Chemotaxis of Lyn-deficient neutrophils was similar to that of PtprjTM–/TM– neutrophils (that is, enhanced relative to that of wild-type cells), whereas Lyn-, Hck-, and Fgr-deficient cells responded similarly to Ptprc–/– neutrophils. Consistent with the ability of CD148 to dephosphorylate an inhibitory tyrosine residue in Lyn, phosphorylation of the inhibitory residue was greater in extent in Ptprc–/– neutrophils than in Ptprc–/–PtprjTM–/TM– doubly deficient neutrophils. Together, these data suggest that CD148 and CD45 exert opposing influences on fMLF-induced migration of neutrophils through their differential regulation of Lyn and Hck/Fgr, respectively.

J. W. Zhu, K. Doan, J. Park, A. H. Chau, H. Zhang, C. A. Lowell, A. Weiss, Receptor-like tyrosine phosphatases CD45 and CD148 have distinct functions in chemoattractant-mediated neutrophil migration and response to S. aureus. Immunity 35, 757–769 (2011). [PubMed]