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Molecular and Cellular Biology, June 2001, p. 3763-3774, Vol. 21, No. 11
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.11.3763-3774.2001
Vav1 Regulates Phospholipase C
Activation and
Calcium Responses in Mast Cells
Timothy Scott
Manetz,1
Claudia
Gonzalez-Espinosa,1
Ramachandran
Arudchandran,1
Sandhya
Xirasagar,1
Victor
Tybulewicz,2 and
Juan
Rivera1,*
Section on Chemical Immunology, National Institute of
Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health, Bethesda, Maryland
20892-1820,1 and the National Institute
for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA,
United Kingdom2
Received 3 November 2000/Returned for modification 12 December
2000/Accepted 7 March 2001
The hematopoietic cell-specific protein Vav1 is a substrate of
tyrosine kinases activated following engagement of many receptors, including Fc
RI. 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 Fc
RI, Syk,
and LAT (linker for activation of T cells) was normal. In contrast,
tyrosine phosphorylation of phospholipase C
1 (PLC
1) and PLC
2
and calcium mobilization were markedly inhibited. Reconstitution of
deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLC
1 and PLC
2 and calcium responses. Thus, Vav1 is essential to Fc
RI-mediated activation of PLC
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 PLC
-activated calcium signals.
*
Corresponding author. Mailing address: NIAMS/NIH,
Building 10, Room 9N228, 10 Center Dr., MSC 1820, Bethesda, MD
20892-1820. Phone: (301) 496-7592. Fax: (301) 402-0012. E-mail:
juan_rivera{at}nih.gov.
Molecular and Cellular Biology, June 2001, p. 3763-3774, Vol. 21, No. 11
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.11.3763-3774.2001
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