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

doi:10.1084/jem.191.1.47

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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 Arudchandran^a, Martin J. Brown^b, Matthew J. Peirce^a, James S. Song^a, Juan Zhang^c, Reuben P. Siraganian^c, Ulrich Blank^d, and Juan Rivera^a

^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 nucleotideexchange factor (GEF) whose activation is mediated by receptorengagement. The relationship of Vav localization to its functionis presently unclear. We found that Vav redistributes to theplasma membrane in response to Fc $isin$ receptor I (Fc $isin$ RI) engagement.The redistribution of Vav was mediated by its Src homology 2(SH2) domain and required Syk activity. The Fc $isin$ RI and Vav werefound to colocalize and were recruited to glycosphingolipid-enrichedmicrodomains (GEMs). The scaffold protein, linker for activationof T cells (LAT), and Rac1 (a target of Vav activity) were constitutivelypresent in GEMs. Expression of an SH2 domain–containingCOOH-terminal fragment of Vav inhibited Vav phosphorylationand movement to the GEMs but had no effect on the tyrosine phosphorylationof the adaptor protein, SLP-76 (SH2 domain–containingleukocyte protein of 76 kD), and LAT. However, assembly of themultiprotein complex containing these proteins was inhibited.In addition, Fc $isin$ RI-dependent activation of c-Jun NH₂-terminalkinase 1 (JNK1) was also inhibited. Thus, Vav localization tothe plasma membrane is mediated by its SH2 domain and may serveto regulate downstream effectors like JNK1.

Key Words: Vav • Fc $isin$ 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 exchangefactor; GEM, glycosphingolipid-enriched microdomain; GFP, greenfluorescent protein; HSA, human serum albumin; ITAM, immunoreceptortyrosine-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–containingleukocyte protein of 76 kD; TCA, trichloroacetic acid.

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