VAV - FUNCTION AND REGULATION IN HEMATOPOIETIC-CELL SIGNALING

Vav, a 95 kDa proto-oncogene product expressed specifically in hematop oietic cells, was originally isolated as a transforming human oncogene . Vav contains an array of functional domains that are involved in int eractions with other proteins and, possibly, with lipids, These includ e, among others, a putative guanine nucleotide exchange domain, a cyst eine-rich region similar to the phorbol ester/diacylglycerol-binding d omain of protein kinase C, a pleckstrin-homology domain, and Src-homol ogy 2 and 3 (SH2 and SH3, respectively) domains, The presence of these domains, the transforming activity of the vav oncogene, and the rapid increase in tyrosine phosphorylation of Vav induced by triggering of diverse receptors indicate that it plays an important role in hematopo ietic cell signaling pathways, Such a role is supported;by recent stud ies using ''knockout'' mice and transiently transfected T cells, in wh ich Vav deletion or overexpression, respectively, had marked effects o n lymphocyte development or activation. The presence of a putative gua nine nucleotide exchange domain, the prototype of which is found in th e dbl oncogene product, implies that Vav functions as a guanine nucleo tide exchange factor (GEF) for one (Or more) members of the Ras-like f amily of small GTP-binding proteins, In support of such a role, Vav pr eparations were found in some (but not other) studies to mediate in vi tro-specific GEF activity for Ras. Additional studies are required to identify the physiological regulators and targets of Vav, and its exac t role in hematopoietic cell development and signaling.