Abstract
Vav guanine nucleotide exchange factor 3 (Vav3), a Rho family GTPase, regulates multiple cell signaling pathways including those of T- and B-cell receptors in vertebrates through mediating the activities of the Rho family members. Whether the lamprey possesses Vav3 homolog and what role it plays in immune response remain unknown. Gene cloning, recombinant expression, antibody production and expression pattern analyses were performed to characterize the lamprey Vav3 in the current study. The lamprey Vav3 is closer to jawed vertebrates’ Vav3 molecules (about 53% identities in general) than to Vav2 molecules of jawless and jawed vertebrates (about 51% identities in general) in sequence similarity. Conserved motif analysis showed that the most distinguished parts between Vav3 and Vav2 proteins are their two Src-homology 3 domains. The relative expression levels of lamprey vav3 mRNA and protein were significantly up-regulated in lamprey lymphocytes and supraneural myeloid bodies after mixed-antigens stimulation, respectively. In addition, lamprey Vav3 were up-regulated drastically in lymphocytes and supraneural myeloid bodies after lipopolysaccharide (LPS) rather than phytohemagglutinin (PHA) stimulation. Lamprey Vav3 distributed in the cytoplasm of variable lymphocyte receptor B positive (VLRB+) lymphocytes, and the number of plasmacytes (VLRB and lamprey Vav3 double positive) in blood lymphocytes also increased after LPS stimulation. Our results proved that lamprey Vav3 was involved in the LPS-mediated immune reaction of lamprey and provided a clue for the further study of the precise role lamprey Vav3 played in the signaling pathway of lamprey VLRB+ lymphocytes.
Highlights
Vav family proteins are a group of guanosine nucleotide exchange factors that contain Dbl homology (DH) domains and possess catalytic activity directed towards Rho- and Rac-GTPases
Lamprey Vav3 is grouped together with lamprey Vav2 as two single branches in the cluster of Vav2 sequences, and the genetic distance between lamprey Vav3 and the common ancestor of Vav2 molecules and lamprey Vav2 is closer than that between lamprey Vav3 and the ancestor of Vav3 molecules. These results indicate that lamprey Vav3 might originate from a common ancestor who was close to Vav2 in genetic distance through a gene duplication process
We found that lamprey Vav3 distribute in VLRB+ lymphocytes and are up-regulated in the lymphocytes and supraneural myeloid bodies after LPS or mixed-antigens stimulation
Summary
Vav family proteins are a group of guanosine nucleotide exchange factors that contain Dbl homology (DH) domains and possess catalytic activity directed towards Rho- and Rac-GTPases. The CH domain is proven to be involved in both the regulation of Vav guanosine nucleotide exchange factor activity and the pathway of Ca2+ mobilization. The Ac domain, which contains three highly conserved tyrosine residues (Y), is an auto-inhibition mediator of Vav guanosine nucleotide exchange factor activity. The DH domain of Vav can interact with Racand Rho-GTPases to promote GDP exchange to GTP. The PH domain is the interaction site for Vav interacting with GTP binding protein, lipid and the phosphorylated serine/threonine residues. The CSH3 domains of Vavs are included in binding their interactive proteins, and there are differences in the protein spectrum that they bind [11,12]
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