Key Points
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The VAV proteins belong to the DBL family of RHO guanine nucleotide exchange factors (GEFs) and are known to have an important role in regulating early events in receptor signalling.
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The domains of VAV proteins that are required for their recruitment to activated receptors on lymphocytes, as well as the domains that regulate their GEF activity, are discussed.
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The physiological importance of the VAV proteins for the development and function of cells of the immune system has been revealed by gene-targeting experiments.
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VAV proteins function in GTPase-dependent and -independent ways. GTPase-dependent aspects of VAV-mediated signalling include a role in signalling events downstream of cytoskeletal reorganization, VAV-mediated control of gene expression and interactions with TEC-family kinases. VAV proteins also have GEF-independent functions.
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The VAV family of proteins is, therefore, crucial for the regulation of immune-cell development and activation.
Abstract
In recent years, substantial progress has been made towards the identification of intracellular signalling molecules that couple multi-subunit immune-recognition receptors (MIRRs) to their various effector functions. Among these, the VAV proteins have been observed to have a crucial role in regulating some of the earliest events in receptor signalling. VAV proteins function, in part, as guanine-nucleotide exchange factors (GEFs) for the RHO/RAC family of GTPases. This review focuses on the role of VAV proteins in the regulation of lymphocyte development and function, and emphasizes the regulatory roles that these proteins have through both GEF-dependent and -independent mechanisms.
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Acknowledgements
We thank L. Clayton for assistance with the figures, P. Leibson for critical review of the manuscript and R. T. Abraham, T. Kurosaki, W. Swat and V. J. L. Tybulewicz for the communication of results before publication.
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Glossary
- SIGNALOSOME
-
A putative, stable signalling complex, which consists of BTK, BLNK, BCAP, VAV1, VAV2, PLC-γ2 and PI3K, that is proposed to regulate the level of intracellular calcium and subsequent downstream events.
- PALMITOYLATION
-
The post-translational addition of C16 palmitates to cysteine residues by a thioester bond targets proteins to specific membrane microdomains.
- ALLELIC EXCLUSION
-
This process by which the successful rearrangement and expression of an antigen-receptor subunit prevents rearrangement at the other allele.
- TONIC SIGNALLING
-
A survival signal that arises as a consequence of antigen-receptor expression that is insufficient to give rise to cell activation.
- THYMUS-DEPENDENT ANTIGENS
-
Antigenic stimuli that require the function of thymus-derived lymphocytes to generate a humoral immune response.
- CLASS SWITCHING
-
The somatic recombination process by which immunoglobulin isotypes are switched from IgM to IgG or IgA.
- THYMUS-INDEPENDENT ANTIGENS
-
Antigenic stimuli that promote humoral immune responses in the absence of thymus-derived lymphocytes.
- SYSTEMIC ANAPHYLAXIS
-
Acute hypersensitivity shock that occurs after the exposure of sensitized animals to antigen.
- IMMUNOLOGICAL SYNAPSE
-
A structure that is formed at the cell surface between a T cell and an antigen-presenting cell; also known as the supra-molecular activation cluster (SMAC). Important molecules involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate at this site. Mobilization of the actin cytoskeleton of the cell is required for immunological-synapse formation.
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Turner, M., Billadeau, D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol 2, 476–486 (2002). https://doi.org/10.1038/nri840
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DOI: https://doi.org/10.1038/nri840
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