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Function
Vav1 is a Guanine Exchange Factor (GEF) for the Rho/Rac protein family [3].
It is involved in cellular response to external stimuli, by inducing cytoskeletal rearrangement or by inter-mediating pathways cascades. As such, the proto-oncogene encoded Vav1 protein has a role in growth and division of the cell, but also in apoptotic pathways.
Vav1 is mainly found in hematopoietic cells [4] and is involved in the differentiation of T lymphocytes, then in B and T cells development and maturation [5].
Vav1 also has a role in Ca2+ induced signalling pathways in immune response of B and T cells.
HIV-1 Nef protein has been found to bind specifically to Vav1, affecting its nucleus-to-cytoplasm distribution, and thus delaying the immune reaction [6]
Disease
Relevance
Structural highlights
The Vav1 are (from N ter to C ter): a calponin-homology (CH) domain, an acidic (Ac) domain, a DBL-homology (DH) domain also known as a rhoGEF domain, a pleckstrin-homology (PH) domain, a phorbol esters/diacylglycerol binding (C1) domain also called Zinc-finger domain and Src-homology (SH) 3 and 2 domains. [7] [8]
(residues 1 - 119): When the CH domain is deleted, Vav has a partial phosphorylation-independant GEF activity. [9]
(residues 134 - 187): contains the Tyrosine (Y174) which activates Vav when phosphorylated. [10]
(residues 194 - 373): present in every Rho/rac GEF, it is the active site of the GTP exchange with the C1 domain in Vav and it promotes the binding to rho GTPase with the help of the C1 domain. It always has a PH domain just after its C terminal.[11]
(residues 402 - 504): point mutation in it don't change the exchange activity of Vav, so it isn't directly involved in its GEF function [12]. But the presence of phosphatidylinositol-4,5-bisphosphate (PIP 2) inhibits 90% of Vav activity while phosphatidylinositol-3,4,5-trisphosphate doubles it. It is very likely that the interactions between these lipids and Vav happen on the PH domain, as it is commonly the case on other proteins with this region. It should be noted that the activation of Vav is made in parallel of the one of PI3-kinase in TCR and BCR pathway. [13]
(508 - 584) : has a cooperative action with the DH domain to bind to the rho GTPase and to promote the GEF activity of Vav.
Src-homology domains SH3-SH2-SH3 (residues 617 - 842): the activators of Vav like Syk or ZP-70 fix on its SH2 region [14]. Potential inhibitors of Vav also dock on its SH3-SH2-SH3 region, such as SHP which would remove the phosphate on Y174 [15] or Cbl-b [16]. It has also been proven that the C-ter SH3 was involved in the auto-inhibition of Vav. [17]
Auto-inhibition and activation
Vav activity
Upon antigen recognition in BCR and TCR pathways, Src family kinases phosphorylate Y174 residue of Vav1. Activated Vav1 can then express its GEF activity on Rac1 [18].
