The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/47/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 47-60

Original Article

The Src Homology 2 Domain of Vav Is Required for Its Compartmentation to the Plasma Membrane and Activation of C-Jun Nh2-Terminal Kinase 1

Ramachandran Arudchandrana, Martin J. Brownb, Matthew J. Peircea, James S. Songa, Juan Zhangc, Reuben P. Siraganianc, Ulrich Blankd, and Juan Riveraa

a Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, the
b Experimental Immunology Branch, National Cancer Institute,
c Laboratory of Immunology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892
d Institut Pasteur, Paris 75724, France
Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bldg. 10, Rm. 9N228, 10 Center Dr., MSC 1820, Bethesda, MD 20892-1820.301-402-0012301-496-7592

juan-rivera{at}nih.gov

Vav is a hematopoietic cell–specific guanine nucleotide exchange factor (GEF) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav redistributes to the plasma membrane in response to Fcisin receptor I (FcisinRI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The FcisinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs). The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs. Expression of an SH2 domain–containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain–containing leukocyte protein of 76 kD), and LAT. However, assembly of the multiprotein complex containing these proteins was inhibited. In addition, FcisinRI-dependent activation of c-Jun NH2-terminal kinase 1 (JNK1) was also inhibited. Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.

Key Words: Vav • Fcisin receptor I • mast cell • glycosphingolipid-enriched microdomains • plasma membrane

Abbreviations used in this paper: CH, calponin homology; DH, Dbl homology; DNP, dinitrophenyl; GEF, guanine nucleotide exchange factor; GEM, glycosphingolipid-enriched microdomain; GFP, green fluorescent protein; HSA, human serum albumin; ITAM, immunoreceptor tyrosine-based activation motif; JNK, c-Jun NH2-terminal kinase; LAT, linker for activation of T cells; PH, pleckstrin homology; SH, Src homology; SFV, Semliki Forest virus; SLP-76, SH2 domain–containing leukocyte protein of 76 kD; TCA, trichloroacetic acid.

© 2000 The Rockefeller University Press


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