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  • Review Article
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The insider's guide to leukocyte integrin signalling and function

Key Points

  • 'Inside-out' signalling causes integrins such as lymphocyte function-associated antigen 1 (LFA1; also known as αLβ2 integrin) to switch from a bent form to an extended form that more easily binds ligand. LFA1 binding to intercellular adhesion molecule 1 (ICAM1) then initiates 'outside-in' signalling that induces T cell functions such as firm adhesion and motility. The rate of conformational change is also affected by physical forces encountered by T cells, such as shear stress owing to vascular flow.

  • Chemokine receptors, the T cell receptor and selectins are the best-studied initiators of inside-out signalling leading to LFA1 activation. Key pathway members are the GTPase RAP1, its appropriate guanine nucleotide exchange factors, talin, kindlin 3 (also known as FERMT3) and phosphatidylinositol-4-phosphate 5-kinase type 1γ87, which produces phosphatidylinositol-4,5-bisphosphate.

  • Recycling vesicles have an important role in inside-out activation by delivering LFA1 and RAP1, complexed with RAPL (regulator of adhesion and cell polarization enriched in lymphoid tissues; also known as RASSF5) and several other proteins, to the plasma membrane.

  • As a result of inside-out signalling, conformational changes occur in the cytoplasmic tails of LFA1 that favour its extension. At the end of the inside-out signalling stage some components are positioned optimally for rapid deployment in the next stage of outside-in signalling.

  • Outside-in signalling occurs when LFA1 binds to its ligand ICAM1, causing phosphorylation of the SRC or spleen tyrosine kinase (SYK) family kinases LCK and ζ-chain-associated protein kinase of 70 kDa (ZAP70), and this leads to the production of high-affinity LFA1. It seems feasible that ZAP70 makes talin accessible for this step by uncoupling a talin–VAV1 complex through VAV1 phosphorylation.

  • The scaffold-type protein kindlin 3 that is mutated in leukocyte adhesion deficiency type III is essential for the activation of LFA1. Its role is incompletely defined but it enables talin binding either directly or indirectly.

Abstract

The activation of leukocyte integrins through diverse receptors results in transformation of the integrin from a bent, resting form to an extended conformation, which has at least two states of ligand-binding activity. This highly regulated activation process is essential for T cell migration and the formation of an immunological synapse. The signalling events that drive integrin activation are complex. Some key players have been well-characterized, but other aspects of the signalling mechanisms involved are still unclear. This Review focuses on the integrin lymphocyte function-associated antigen 1 (LFA1; also known as αLβ2 integrin), which is expressed by T cells, and explores how disparate signalling pathways synergize to regulate LFA1 activity.

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Figure 1: Different conformations of LFA1 and the role of mechanical force in effecting LFA1 activation.
Figure 2: Essential stages of inside-out signalling.
Figure 3: Outside-in signalling pathway follows LFA1 binding to ICAM1.
Figure 4: Selectin inside-out signalling leads to intermediate-affinity LFA1 and slow rolling.

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Acknowledgements

We thank our colleagues in the Leukocyte Adhesion Lab for useful comments and T. Kinashi and M. Philips for helpful discussion. Our research is funded by Cancer Research UK; F.W. is supported by the Wellcome Trust.

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Correspondence to Nancy Hogg.

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Glossary

Immunological synapses

Stable regions of contact between T cells and antigen-presenting cells that are held together by adhesive interactions between lymphocyte function-associated antigen 1 (LFA1) and intercellular adhesion molecule 1 (ICAM1) on the respective cell types. The mature T cell immunological synapse contains two distinct, stable membrane domains: a central cluster of T cell receptors, called the central supramolecular activation cluster (cSMAC), and a surrounding adhesive ring that incorporates LFA1, called the peripheral supramolecular activation cluster (pSMAC).

Shear flow or buffeting

Shear force from the flow of blood in the vasculature disrupts the interactions between the lymphocyte function-associated antigen 1 (LFA1) ectodomains causing leg separation and favouring the extended open conformation, which can then rapidly bind to intercellular adhesion molecule 1 (ICAM1). Buffeting has been proposed to result from rapid lateral movement of the actin cytoskeleton with attached LFA1 in the lamellipodium of migrating cells. This would cause LFA1 to collide with the numerous other glycoproteins on the cell surface and has a similar effect to shear force, disrupting the compact bent lower affinity forms of the molecule.

Catch bond

A non-covalent bond that has a longer lifetime in the presence of tensile force. The off-rates of these bonds are decreased with increasing force until a maximum force is reached, when they revert to 'slip bonds' (the off-rates of which increase with increasing force).

RAP1

A small GTPase that cycles between an active GTP-bound form and an inactive GDP-bound form. It is activated by guanine nucleotide-exchange factors (GEFs) that displace GDP, allowing GTP to bind. The RAP1 GEFs expressed in leukocytes are C3G and CALDAGGEF1. A third common RAP1 GEF is EPAC but this has not been extensively investigated in leukocytes.

RIAM

(RAP1–GTP-interacting adaptor molecule; also known as APBB1IP). A 110 kDa protein that contains an N-terminal RAS-associated domain, a coiled-coil domain, a pleckstrin homology (PH) domain and a proline-rich C-terminal domain with six FPPPP motifs that binds to profilin and Ena and VASP family proteins.

Talin

A cytoskeletal protein of 270 kDa. It consists of an N-terminal globular head domain (50 kDa) that contains four FERM subdomains and a longer C-terminal rod domain (220 kDa) that includes actin and vinculin binding sites. The FERM3 subdomain contains a phosphotyrosine-binding (PTB) domain that binds the β-subunit of integrins at the membrane-proximal NPXY site. The talin FERM domain has unique properties compared with other PTB domain-containing proteins, as it has a second binding site on the β-subunit tail in closer proximity to the membrane.

FERM domain

(Protein 4.1, ezrin, radixin and moesin domain). A region that is present as a domain in proteins such as talin, but comprises the entire molecule in proteins such as the kindlins. This region has four subdomains: F0, F1, F2 and F3. Subdomain F3 contains a phosphotyrosine-binding motif that targets NXXY sites on the β-subunit tail of integrins. FERM domains lack their own intrinsic activity and are essentially scaffold domains.

Kindlin 3

(Also known as FERMT3). The kindlin family has three members (kindlins1, 2 and 3), with kindlin 3 expressed exclusively in cells of haematopoietic origin. Kindlin 3 comprises a 72 kDa FERM domain composed of four subdomains. FERM subdomain 2 is bisected with a pleckstrin homology (PH) domain that is potentially involved in membrane binding and FERM subdomain 3 binds the membrane-distil NXXY motif on the β-subunit of β1, β2 and β3 integrins.

PIP5K1γ87

Phosphatidylinositol-4-phosphate 5-kinase type 1γ87 is one of three splice variants of PIP5K1γ. It functions downstream of phospholipase D and generates PtdIns(4,5)P2 as a major product.

C3G

(Also known as RAPGEF1). A RAP1 guanine nucleotide-exchange factor expressed by leukocytes, including T cells. C3G contains a proline-rich domain that constitutively interacts with the SH2 domain of CRKL in T cells. In T cells, the activity of the C3G–CRKL complex is negatively regulated by the E3 ubiquitin ligase CBLB.

CALDAG-GEF1

(Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor1; also known as RASGRP2). A RAP1 guanine nucleotide-exchange factor (GEF) found in human but not mouse T cells. This protein contains a RAS exchange motif, a diacylglycerol-binding C1 domain, two EF hand Ca2+-binding domains and a GEF domain.

RAPL

(Regulator of adhesion and cell polarization enriched in lymphoid tissues; also known as RASSF5). This protein contains a RAP1-binding domain and a C-terminal coiled-coil domain for protein interactions.

MST1

(Mammalian STE20-like protein kinase 1; also known as STK4). A homodimeric serine/threonine kinase that is homologous to the yeast protein sterile 20 and to the Drosophila melanogaster protein Hippo. This protein contains an N-terminal kinase domain and a C-terminal regulatory domain. MST1 binds to the RAPL C-terminal coiled-coil domain, which potentially destabilizes the MST1 homodimer, inducing activating autophosphorylation.

SKAP55

(SRC kinase-associated phosphoprotein of 55 kDa; also known as SKAP1). This protein contains an N-terminal pleckstrin homology (PH) domain and C-terminal non-canonical SH3 domains. SKAP55 interacts with ADAP, which prevents its degradation.

PLD1

Phospholipase D1 functions downstream of RHO family GTPases and is activated following chemokine signalling. Its product, phosphatidic acid, regulates PIP5K1γ87 activity.

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Hogg, N., Patzak, I. & Willenbrock, F. The insider's guide to leukocyte integrin signalling and function. Nat Rev Immunol 11, 416–426 (2011). https://doi.org/10.1038/nri2986

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