SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils.
While the contribution of intracellular adaptor proteins to lymphocyte activation has been well studied, the function of these molecules in innate immune effector cells such as neutrophils has not been extensively addressed. Here we demonstrate a critical role for the adaptor molecule SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) in FcgammaR and integrin signaling. Stimulation of these receptors induces tyrosine phosphorylation and cytoplasmic relocalization of SLP-76 in freshly isolated murine neutrophils. Neutrophils lacking SLP-76 demonstrate decreased FcgammaR-induced calcium flux and reactive oxygen intermediate (ROI) production in response to immune complex stimulation. More dramatically, SLP-76-/- neutrophils fail to produce ROI, spread, or activate critical downstream regulators in response to integrin ligation. These results provide genetic evidence for a critical role of SLP-76 in the regulation of neutrophil function.
Newbrough
Sally A
SA
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mocsai
Attila
A
Clemens
Regina A
RA
Wu
Jennifer N
JN
Silverman
Michael A
MA
Singer
Andrew L
AL
Lowell
Clifford A
CA
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018390:Gene Targeting; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000378:metabolism* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C499172:Fcgr2b protein, mouse; D016023:Integrins; D010750:Phosphoproteins; D017452:Receptors, IgG; C092947:SLP-76 signal Transducing adaptor proteins; D014443:Tyrosine