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Intracellular signalling controlling integrin activation in lymphocytes

Nature Reviews Immunology volume 5, pages 546–559 (2005)Cite this article

Key Points

  • Regulation of integrin avidity by inside-out signals (that is, intracellular signals that alter the avidity of integrins at the cell surface) occurs in two ways: regulation of integrin affinity, and regulation of integrin diffusion and clustering in the cell membrane (which is known as valency regulation).

  • Regulation of integrin conformation by the 'switch-blade model' of integrin activation leads to changes in integrin affinity. The cytoplasmic tail of integrins is crucial for transmitting the inside-out signals that induce this conformational change.

  • Inside-out signalling pathways that involve phosphatidylinositol 3-kinase, RHO (RAS homologue), RAP1, RAPL and DOCK2 (dedicator of cytokinesis 2) mediate chemokine-induced modulation of LFA1 (lymphocyte function-associated antigen 1) avidity.

  • Inside-out signalling pathways that involve TEC-family kinases, VAV1, ADAP (adhesion- and degranulation-promoting adaptor protein), RAP1 and RAPL mediate T-cell-receptor-triggered modulation of LFA1 avidity and formation of an immunological synapse.

  • Talin — a 250 kDa cytoskeletal protein that links integrins and the actin cytoskeleton — might be involved in inside-out signalling pathways that regulate lymphocyte adhesion.

  • RHO-H negatively regulates inside-out signalling pathways that increase integrin avidity.

  • A model of regulation of lymphocyte adhesion, based on the control of intracellular trafficking and the development of cell polarity, is discussed.

Abstract

Since the discovery that integrins at the surface of lymphocytes undergo dynamic changes in their adhesive activity after stimulation through the T-cell receptor or stimulation with chemokines, intensive research has been carried out in an attempt to clarify the signalling events that lead to the activation of integrins. Whereas structural studies have provided us with a vivid picture of the conformational flexibility of integrins, the signalling pathways that regulate these conformational changes (known as inside-out signalling) have been elusive. However, as I discuss here, recent studies have provided new insight into the pathways that control the regulation of integrin activity and the coordination of complex cellular functions, such as the homing of lymphocytes and the formation of an immunological synapse.

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Figure 1: The integrin family.
Figure 2: Integrin structure and regulation.
Figure 3: The adhesion cascade, from rolling to diapedesis.
Figure 4: Inside-out signalling pathways.
Figure 5: T-cell-receptor signalling that results in integrin activation and immunological-synapse formation.
Figure 6: A model of the regulatory processes that control integrin function.

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Acknowledgements

I thank the reviewers and my colleague K. Katagiri for valuable comments and discussion.

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Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medicine, Institute of Liver Research, Kansai Medical School, 10–15 Fumizono-cho, Moriguchi, Osaka, 570-8506, Japan

    Tatsuo Kinashi

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DATABASES

Entrez Gene

ADAP

DOCK2

α4β7-integrin

ITK

LFA1

RAC

RAP1

RAPL

RHO-A

RHO-H

talin

VAV1

VLA4

Glossary

MICROCLUSTER

A small aggregate of integrins. These are found scattered around the cell surface.

PATCH-LIKE CLUSTER

A large aggregate of integrins. These form on one side of the cell.

SALT BRIDGE

A type of molecular force that connects two oppositely charged atoms or groups of atoms by electrostatic interactions: for example, when an arginine residue, which is positively charged, binds a glutamic-acid residue, which is negatively charged.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A physical phenomenon that can occur when two fluorophores come into close proximity (1–10 nm) and energy from one is transferred to the other without emission of a photon.

HIGH ENDOTHELIAL VENULE

(HEV). A specialized venule with a cuboidal endothelial lining. It is found in peripheral lymph nodes and Peyer's patches. HEVs are sites at which naive lymphocytes enter lymphoid tissues.

MULTI-PHOTON MICROSCOPY

(Multiple-photon excitation fluorescence microscopy). A technique that uses non-linear optical effects to achieve optical sectioning. Compared with conventional imaging methods, it is less toxic to thick living-tissue samples because it uses infrared light, which is of lower energy; in addition, it is more penetrating because infrared light is scattered less as it enters the sample.

UROPOD

A slender protrusion that forms at the rear of migrating leukocytes.

PLECKSTRIN-HOMOLOGY DOMAIN

A domain of ∼100 amino acids that can bind inositol phosphates or proteins.

GUANINE-NUCLEOTIDE EXCHANGE FACTOR

(GEF). A factor — such as a member of the RAS or RHO (RAS homologue) families — that promotes the exchange of GDP that is bound to GTP-binding proteins for GTP.

ADP-RIBOSYLATION-FACTOR FAMILY

(ARF family). A family of small GTPases. These molecules are involved in the regulation of the actin cytoskeleton and coated-vesicle formation.

PHORBOL ESTER

A phorbol moiety that has been esterified by combination with a long hydrocarbon chain. These compounds are analogues of diacylglycerol.

LEUKOCYTE-ADHESION DEFICIENCY

(LAD). A rare hereditary disease in humans that is characterized by recurrent infection and delayed wound healing as a consequence of defective leukocyte adhesion. There are two types of LAD: type I is caused by mutations of β2-integrin; and type II is caused by a defect in fucose metabolism that results in a failure to express the ligand for endothelial-cell selectin (E-selectin) and platelet selectin (P-selectin), sialyl-Lewis X.

RASSF TUMOUR-SUPPRESSOR FAMILY

A family of proteins that contain a RAS-association domain and are thought to be involved in apoptosis and carcinogenesis. Not all proteins that contain the RAS-association domain bind RAS or RAP1.

SMALL INTERFERING RNA

(siRNA). Sequences of 21–23 nucleotides that are recruited to a ribonuclease complex (known as the RNA-induced silencing complex), which in turn mediates the cleavage of the specific target mRNA.

CDM

A family of proteins that is represented by Caenorhabditis elegans CED-5 (cell-death abnormality 5), human DOCK1 (dedicator of cytokinesis 1) and Drosophila melanogaster myoblast city. These proteins function upstream of RAC to regulate membrane extension, cell migration and phagocytosis of dead cells.

R-RASGAP

(R-RAS (related to RAS) GTPase-activating protein). A GTPase-activating protein that is specific for R-RAS. It hydrolyses GTP to GDP by stimulating the GTPase activity of R-RAS.

TEC FAMILY

A family of non-receptor protein tyrosine kinases that contain a pleckstrin-homology domain. The prototype members are ITK (interleukin-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. TEC-family kinases are involved in the intracellular-signalling mechanisms of cytokine receptors, lymphocyte antigen receptors, heterotrimeric G-protein-coupled receptors and integrins.

VIABLE MOTHEATEN MICE

Viable motheaten (mev/mev) mice have a mutation in the coding region of the catalytic domain of SHP1 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1), which results in two aberrant loss-of-function proteins (one of 67 kDa and one of 71 kDa). These mice develop severe combined immunodeficiency and systemic autoimmunity.

ANERGY

A state of T-cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of engagement of co-stimulatory molecules.

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Kinashi, T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 5, 546–559 (2005). https://doi.org/10.1038/nri1646

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