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  • Review Article
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VAV proteins as signal integrators for multi-subunit immune-recognition receptors

Nature Reviews Immunology volume 2, pages 476–486 (2002)Cite this article

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Figure 1: Mechanism of action of VAV proteins.
Figure 2: VAV and the signalosome.

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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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Authors and Affiliations

  1. Lymphocyte Signalling and Development Laboratory, Molecular Immunology Programme, The Babraham Institute, Babraham, CB2 4AT, Cambridge, UK

    Martin Turner

  2. Division of Developmental Oncology Research and the Department of Immunology, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Daniel D. Billadeau

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DATABASES

Entrez

HIV-1

Listeria monocytogenes

Nef

InterPro

CH domain

DH domain

ITAM

PH domain

SH2 domain

SH3 domain

WW motif

LocusLink

AP1

β2-microglobulin

BLNK

Btk

Cbl-b

CD3

CD4

CD19

CD28

CDC42

Cdc42

cyclin D2

DBL

FAS ligand

FcɛRI

FYN

Gads

GRB2

HCK

IFN-γ

IκBα

IKK

IL-2

IL-4

Itk

LAT

LCK

NFAT

NF-κB

PAK1

PI3K

PIP5K

PKCθ

PLC-γ1

PLC-γ2

RAC1

Rac1

RAC2

RHOA

RhoA

RHOB

RHOG

Rlk

SLP76

Slp76

SRC

SYK

Tec

vav

VAV1

Vav1

VAV2

Vav2

VAV3

Vav3

ZAP70

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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