Differential requirement for adapter proteins Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and adhesion- and degranulation-promoting adapter protein in FcepsilonRI signaling and mast cell function.
The adapter molecule Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is essential for FcepsilonRI-mediated signaling, degranulation and IL-6 production in mast cells. To test the structural requirements of SLP-76 in mast cell signaling and function, we have studied the functional responses of murine bone marrow-derived mast cells (BMMCs) expressing mutant forms of SLP-76. We found that the N-terminal tyrosines as well as the central proline-rich region of SLP-76 are required for participation of SLP-76 in FcepsilonRI-mediated signaling and function. The C-terminal SH2 domain of SLP-76 also contributes to optimal function of SLP-76 in mast cells. Another adapter molecule, adhesion- and degranulation-promoting adapter protein (ADAP), is known to bind the SH2 domain of SLP-76, and cell line studies have implicated ADAP in mast cell adhesion and FcepsilonRI-induced degranulation. Surprisingly, we found that mast cells lacking ADAP expression demonstrate no defects in FcepsilonRI-induced adhesion, granule release, or IL-6 production, and that ADAP-deficient mice produce a normal passive systemic anaphylactic response. Thus, failure to bind ADAP does not underlie the functional defects exhibited by SLP-76 SH2 domain mutant-expressing mast cells.
Wu
Jennifer N
JN
Abramson Family Cancer Research Institute and Department of Laboratory Medicine and Pathology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jordan
Martha S
MS
Silverman
Michael A
MA
Peterson
Erik J
EJ
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000502:physiology*; D000707:Anaphylaxis / Q000209:etiology; D000818:Animals; D002448:Cell Adhesion; D015550:Cell Degranulation; D016207:Cytokines / Q000096:biosynthesis; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D017455:Receptors, IgE / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D010738:Type C Phospholipases / Q000502:physiology; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D010750:Phosphoproteins; D017455:Receptors, IgE; C092947:SLP-76 signal Transducing adaptor proteins; D010738:Type C Phospholipases; D051966:Phospholipase C gamma