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  • Review Article
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Positive and negative regulation of t-cell activation by adaptor proteins

Nature Reviews Immunology volume 1, pages 95–107 (2001)Cite this article

Key Points

  • Adaptor proteins are as crucial as receptors and effectors as regulators of lymphocyte activation.

  • Adaptors serve as positive or negative regulators by nucleating intermolecular complexes and modulating effector protein activity.

  • Techniques to study the biology of adaptors involve genetic manipulation of cell lines and animals, biochemical assessment of intermolecular interactions, and imaging of the temporal and spatial organization of signalling complexes.

  • Adaptor domains within effector molecules may have vital roles for function. For example, SRC family kinases are regulated both by post-translational modifications (e.g. phosphorylation) and by intramolecular interactions mediated by SH2 and SH3 domains.

  • Adaptors may function cooperatively in signalling pathways (e.g. SLP76 and LAT).

  • Subcellular localization of adaptors is key to their function.

Abstract

Adaptor proteins, molecules that mediate intermolecular interactions, are now known to be as crucial for lymphocyte activation as are receptors and effectors. Extensive work from numerous laboratories has identified and characterized many of these adaptors, demonstrating their roles as both positive and negative regulators. Studies into the molecular basis for the actions of these molecules shows that they function in various ways, including: recruitment of positive or negative regulators into signalling networks, modulation of effector function by allosteric regulation of enzymatic activity, and by targeting other proteins for degradation. This review will focus on a number of adaptors that are important for lymphocyte function and emphasize the various ways in which these proteins carry out their essential roles.

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Figure 1: Positive regulation of TCR signalling by adaptor proteins.
Figure 2: Negative regulation of TCR signalling by adaptors.

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 415 BRB II/III, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Gary A. Koretzky & Peggy S. Myung

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  1. Gary A. Koretzky
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Correspondence to Gary A. Koretzky.

Related links

Related links

DATABASES

LocusLink

c-Cbl

CD3

CD28

CD45

CDC42

CSK

Enb

EVL

FYB

FYN

GADS

GAL4

GRB2

Il2

IRSp53

ITK

LAT

LCK

Mena

NCK

NFAT

PAG

PAK1

PLCγ1

PTEN

RAC1

RAP1

Robo

SDF1

SLIT3

SLP76

UBCH7

VASP

VAV1

Vav2

vinculin

WASP

WAVE

ZAP70

zyxin

FURTHER INFORMATION

Gary Koretzky's lab

Glossary

ADAPTOR MOLECULES

Molecules that lack any known intrinsic enzymatic, DNA binding or receptor functions, but mediate protein–protein or protein–lipid interactions. Most function as flexible molecular scaffolds by regulating the spatio-temporal dynamics of specific effector molecules.

PROTEIN TYROSINE KINASES

(PTKs). Enzymes that catalyse the phosphorylation of proteins on tyrosine residues within the context of specific peptide motifs. PTKs can be generally categorized as either receptor PTKs or as cytosolic PTKs (e.g. ZAP70).

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). Regions found within the CD3 chains of the TCR and other immunoreceptors characterized by tyrosine and leucine or isoleucine residues with discrete spacing. Following receptor engagement, the tyrosines are inducibly phosphorylated and become docking sites for SH2 domain containing proteins including SYK-family protein tyrosine kinases.

JURKAT T CELL

Human leukaemic T-cell line used to study several aspects of T-cell biology and signalling — in particular, signal-transduction events initiated by the TCR.

LIPID RAFTS

Micro-aggregates of cholesterol and sphingomyelin thought to occur in the plasma membrane. Also described as glycolipid-enriched membrane microdomains (GEMs) or detergent-insoluble glycosphingolipid-enriched membrane microdomains (DIGs).

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). Proteins that activate low-molecular-mass GTPases, such as RHO-family GTPases and RAS by stimulating the dissociation of GDP, and therefore promoting formation of the active GTP-bound state of these GTPases.

LAMELLIPODIA

Thin sheet-like processes, which extend at the leading edge of moving cells or neuronal growth cones in an actin-dependent fashion; promoted by the RHO-family GTPase, RAC1.

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Koretzky, G., Myung, P. Positive and negative regulation of t-cell activation by adaptor proteins. Nat Rev Immunol 1, 95–107 (2001). https://doi.org/10.1038/35100523

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