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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 Cgamma 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 Fcvarepsilon 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 Fcvarepsilon RI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase Cgamma 1 (PLCgamma 1) and PLCgamma 2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLCgamma 1 and PLCgamma 2 and calcium responses. Thus, Vav1 is essential to Fcvarepsilon RI-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.

* 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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