Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells.
The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcepsilonRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1-deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcepsilonRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase Cgamma1 (PLCgamma1) and PLCgamma2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLCgamma1 and PLCgamma2 and calcium responses. Thus, Vav1 is essential to FcepsilonRI-mediated activation of PLCgamma and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLCgamma-activated calcium signals.
Manetz
T S
TS
Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.
Gonzalez-Espinosa
C
C
Arudchandran
R
R
Xirasagar
S
S
Tybulewicz
V
V
Rivera
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D016207:Cytokines / Q000235:genetics; D004789:Enzyme Activation; D015870:Gene Expression; D007527:Isoenzymes / Q000378:metabolism*; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051567:Proto-Oncogene Proteins c-vav; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002118:Calcium; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051567:Proto-Oncogene Proteins c-vav; D020794:Receptor Protein-Tyrosine Kinases; D017455:Receptors, IgE; D010738:Type C Phospholipases; C491734:Lat protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C496619:Vav1 protein, mouse; C084944:TYRO3 protein, human