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  • Review Article
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Transmembrane adaptor proteins: organizers of immunoreceptor signalling

Nature Reviews Immunology volume 4, pages 603–616 (2004)Cite this article

An Erratum to this article was published on 01 September 2004

Key Points

  • After engagement by their cognate ligands, multichain immunoreceptors that are expressed by haematopoietic cells move into lipid rafts, which are enriched in protein tyrosine kinases of the SRC family. This induces the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) that are present in the cytoplasmic domains of immunoreceptor-associated signal-transducing subunit(s), thereby allowing membrane recruitment and subsequent activation of cytosolic tyrosine kinases belonging to the SYK (spleen tyrosine kinase) family.

  • A new group of integral membrane molecules, known as transmembrane adaptor proteins (TRAPs), has been identified and characterized. This solved the issue of how cytosolic adaptor and effector molecules with SRC homology 2 (SH2) domains become targeted to the cell membrane after immunoreceptor engagement and translate immunoreceptor-mediated signals into the appropriate cellular response.

  • The seven known TRAPs all have a short extracellular domain, a single membrane-spanning region and a long cytoplasmic tail with up to nine tyrosine-based signalling motifs. After immunoreceptor engagement, TRAPs become phosphorylated and then provide the docking sites for SH2-domain-containing proteins.

  • The TRAP LAT (linker for activation of T cells) assembles a multicomponent signalling complex within lipid rafts that connects the T-cell receptor (TCR) to the main intracellular signalling pathways, which then lead to production of the T-cell growth factor interleukin-2.

  • As well as LAT, at least three other TRAPs — NTAL (non-T-cell activation linker), PAG (protein associated with glycosphingolipid-enriched microdomains) and LIME (LCK-interacting membrane protein) — organize membrane-proximal signalling modules that regulate immunoreceptor-mediated signals in the lipid rafts of T cells and non-T cells.

  • Three additional TRAPs — TRIM (TCR-interacting molecule), SIT (SH2-domain-containing protein tyrosine phosphatase (SHP2)-interacting transmembrane adaptor protein) and LAX (linker for activation of X cells, where X denotes an as yet unidentified cell) — reside outside lipid rafts. These three molecules are potentially involved in the negative regulation of TCR-mediated signals.

  • Further analysis of this emerging group of signalling molecules will add to our understanding of the membrane-proximal signalling events that regulate the development, activation and differentiation of haematopoietic cells.

Abstract

Signalling through multichain immunoreceptors is required for the development, activation and differentiation of haematopoietic cells. One of the most challenging questions with regard to these processes is how immunoreceptor-mediated signals are converted into appropriate cellular responses. The recent identification of a novel group of signalling molecules, known as transmembrane adaptor proteins, has led to exciting new insights. The transmembrane adaptor proteins LAT, NTAL, PAG, LIME, TRIM, SIT and LAX organize complex membrane-proximal signalling assemblies and are therefore key mediators of immunoreceptor-mediated signalling. As we discuss here, their identification has greatly facilitated our understanding of how immunoreceptors are connected to intracellular signalling cascades.

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Figure 1: Current model of membrane-proximal immunoreceptor-mediated signalling, using the TCR as an example.
Figure 2: The transmembrane adaptor proteins.
Figure 3: The signalosome organized by LAT.
Figure 4: The role of the PAG–CSK complex in TCR-mediated signalling.
Figure 5: Model of LIME- versus PAG-mediated regulation of SRC-kinase activity.

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Acknowledgements

This work was supported by grants from the German Research Foundation (DFG) to B.S. V.H. is supported by the Center of Molecular and Cellular Immunology, Ministry of Education, Youth and Sports, Czech Republic. W.Z. is supported by grants from the National Institutes of Heath, United States. We thank M. Kliche and M. Togni for their support during the generation of the artwork, and J. Wienands and J. Lindquist for careful reading of the manuscript.

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Authors and Affiliations

  1. Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, 142 20 4, Czech Republic

    Václav Hořejší

  2. Department of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Weiguo Zhang

  3. Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipzigerstrasse 44, Magdeburg, 39120, Germany

    Burkhart Schraven

Authors
  1. Václav Hořejší
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  2. Weiguo Zhang
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  3. Burkhart Schraven
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Correspondence to Burkhart Schraven.

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DATABASES

Entrez Gene

CBL

CD69

CSK

EBP50

ERK

FYN

GAB2

GADS

γ-chain

GRB2

ITK

LAT

LAX

LCK

LIME

LYN

NFAT

NTAL

PAG

RAF

RASGRP

SHP2

SIT

SLP76

SOS

TRIM

ZAP70

ζ-chain

FURTHER INFORMATION

Burkhart Schraven's laboratory

Glossary

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several signalling molecules. The motif has the form YXX(L/I/V)X6-8YXX(L/I/V), where X denotes any amino acid. The tyrosine residues are targets for phosphorylation by SRC-family protein tyrosine kinases and subsequent binding of proteins that contain SRC homology 2 (SH2) domains.

SRC-KINASE FAMILY

A group of structurally related cytoplasmic and/or membrane-associated enzymes named after its prototypical member, SRC. In haematopoietic cells, SRC kinases — such as LCK, FYN and LYN — are the first protein tyrosine kinases to become activated after stimulation through the immunoreceptor. Among other substrates, they phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) that are present in the signal-transducing subunits of the immunoreceptors, thereby providing binding sites for SRC homology 2 (SH2)-domain-containing molecules, such as spleen tyrosine kinase (SYK).

SRC HOMOLOGY 2 (SH2) DOMAINS

Protein domains that are found commonly in signal-transduction molecules. They specifically recognize phosphotyrosine-containing peptide sequences in proteins.

SYK-FAMILY KINASES

The second class of cytoplasmic protein tyrosine kinases that have essential roles in the activation of haematopoietic cells — the other classes being the SRC- and TEC-family kinases. This small group consists of ZAP70 (ζ-chain-associated protein kinase of 70 kDa) in T cells, and SYK (spleen tyrosine kinase) in B cells and myeloid cells. After immunoreceptor ligation, SYKs bind through tandem SRC homology 2 (SH2) domains to the phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs). Subsequently, they become phosphorylated and activated by SRC kinases.

TEC-KINASE FAMILY

A third class of protein tyrosine kinases that is required for the activation of haematopoietic cells — the first and second classes being the SRC- and SYK-family kinases. The TEC-family kinase prototypes are ITK (interleukin-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. Among other functions, TEC kinases seem to have an important role in the activation of phospholipase C enzymes after immunoreceptor ligation.

E3 UBIQUITIN LIGASE

Ubiquitin ligases recruit ubiquitin-conjugating enzymes, which attach the small polypeptide ubiquitin to proteins. The polyubiquitylated proteins are then subjected to proteasomal degradation. Polyubiquitylation, followed by proteasomal degradation, is one of the cellular mechanisms to eliminate proteins.

γδ T CELLS

T cells express either a T-cell receptor (TCR) composed of α- and β-subunits (αβ-TCR) or a TCR composed of γ- and δ-subunits (γδ-TCR). Most human T cells (more than 90%) express αβ-TCRs that mainly recognize antigenic peptides bound to conventional MHC class I or II molecules. T cells that express γδ-TCRs are less abundant, and the ligands for these receptors are less well-characterized.

SH3 DOMAIN

A protein domain that is common in signal-transduction molecules. It interacts specifically with certain proline-containing peptides. Classically, it contains either (R/K)XXPXXP or PXXPXR motifs, where X denotes any amino acid.

ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY

(ADCC). A mechanism by which natural killer (NK) cells kill other cells: for example, virus-infected target cells that are coated with antibodies. The Fc portions of the coating antibodies interact with the Fc receptors (FcγRIII; also known as CD16) that are expressed by NK cells, thereby initiating a signalling cascade that results in the release of cytotoxic granules (containing perforin and granzyme B), which induce apoptosis of the antibody-coated cell.

NATURAL CYTOTOXICITY

Denotes the ability of some cells — mainly natural killer (NK) cells and NKT cells — to kill tumour cells or virus-infected cells after coming into contact with them, without previous deliberate immunization of the host or activation of these immune cells, processes which are required for similar cytotoxic killing by antigen-specific T cells.

RNA INTERFERENCE

(RNAi). A phenomenon in which the expression of a gene is inhibited when a double-stranded complementary RNA molecule is introduced into the organism.

PDZ DOMAIN

A protein domain that is common in signal-transduction molecules. It can interact with different amino-acid motifs that are present at the carboxyl terminus of proteins. PDZ domains can also interact with other PDZ domains, with certain internal peptide sequences and even with lipids.

ERM PROTEINS

Ezrin, radixin, moesin and the closely related merlin are structurally similar cytoplasmic adaptor (linker) proteins that contain an amino-terminal domain able to interact with some membrane-linked proteins or ERM-binding protein 50 (EBP50)-family adaptors. They also have a carboxy-terminal domain that can interact with F-actin. So, the ERM proteins link receptors and other membrane proteins to the actin cytoskeleton.

IMMUNE SYNAPSE

A large junctional structure that is formed at the cell surface between a T cell that is interacting with an antigen-presenting cell. It is also known as the supramolecular activation cluster (SMAC). Important molecules involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Mobilization of the actin cytoskeleton of the cell is required for immune-synapse formation.

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Hořejší, V., Zhang, W. & Schraven, B. Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat Rev Immunol 4, 603–616 (2004). https://doi.org/10.1038/nri1414

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