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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
The major reason why VAV1 is a protein of interest is because it was revealed that many mutants are often implicated in numerous cases of cancer such as implicated in mammalian malignancies, including neuroblastoma, melanoma, pancreatic, lung and breast cancers, and B-cell chronic lymphocytic leukemia and it's frequently overexpressed in tumors whereas it's normally solely expressed in the hematopoietic system[7]. As a regulatory protein, it's involved in many pathways that end up controlling the activity of important transcription factors that influence cell cycle regulation. It's been discovered to take part in the NF-AT pathway[8] as well as the Rac1, PAK1, and NF-kappaB and involve cyclin D1 upregulation[9]. That's why it's now considered as a potentially prooncogenic protein. It's still unsure how mutations of VAV1 affect the risks of cancer and it's been demonstrated that epigenetic changes alone contributed to an aberrant proliferation of cells. It was also discovered that a mutation of VAV1 could weaken the immune response of mammalians, however, no immune disability had been reported yet that involved a deficience with VAV1[10].
diagnostic and therapeutic context
Also VAV1 was already identified as an oncogenic factor, there is still little ways to deal with it. Several studies tried to modulate its activity to slow down or to stop cell proliferation. It's been proved that VAV1 promoter demethylation as an event in cancer progression, suggesting that aberrant signaling pathways driven by VAV1 are potential therapeutic targets in Pancreatic ductal adenocarcinoma[11]. What's more, it's still being researched for now, but it may be possible to use already know antioncogenic coumpounds such as azathioprine would be relevent against mutated VAV1 induced cancers[12].
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. [13] [14]
(residues 1 - 119): When the CH domain is deleted, Vav has a partial phosphorylation-independant GEF activity. [15]
(residues 134 - 187): contains the Tyrosine (Y174) which activates Vav when phosphorylated. [16]
(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.[17]
(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 [18]. 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. [19]
(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 [20]. Potential inhibitors of Vav also dock on its SH3-SH2-SH3 region, such as SHP which would remove the phosphate on Y174 [21] or Cbl-b [22]. It has also been proven that the C-ter SH3 was involved in the auto-inhibition of Vav. [23]
Auto-inhibition and activation
When Tyr-174 on the Ac domain is not phosphorylated, Vav1 is auto-inhibited. It has long been thought that only the CH and Ac domain interactions with the DH, PH and C1/ZN domains played a role in auto-inhibition. Indeed, , forming beta-sheet like hydrogen bonds. There is also a close interaction between the PH and Ac domains, some oppositely charged residues facing each other like Asp-150 on Ac and Lys-487 on PH. [24]
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 [25].
