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

Vav is a hematopoietic cell-specific guanine nucleotide exchange factor (GE F) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav r edistributes to the plasma membrane in response to Fc epsilon receptor I (F c epsilon RI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The Fc epsilon RI and V av were found to colocalize and were recruited to glycosphingolipid-enriche d microdomains (GEMs). The scaffold protein, linker for activation of T cel ls (LAT), and Rad (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 o n the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-c ontaining leukocyte protein of 76 kD), and LAT. However, assembly of the mu ltiprotein complex containing these proteins was inhibited. In addition, Fc epsilon RI-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.