Integrin signalling and function in immune cells

Abstract

Integrins not only mediate cell-cell and cell-extracellular matrix adhesion, but also affect the multitude of signal transduction cascades in control of cell survival, proliferation, differentiation and organ development. Mutations in integrins or the major effectors of integrin signalling pathways cause defective organ development, immunodeficiency, cancer or autoimmune disease. Understanding of the signalling events that drive integrin activation and signalling is therefore crucial to uncover the molecular mechanisms of these diseases. This review discusses the key signalling complexes regulating integrin activation and function in both 'inside-out' and 'outside-in' pathways in T lymphocytes, including kinases, SLP-76, VAV1, ADAP, SKAP-55, RapL, RIAM, Rap1, Talin and Kindlin.

© 2012 Shanghai Institute of Biochemistry and Cell Biology, SIBS, CAS. Immunology © 2012 Blackwell Publishing Ltd.

Figures

Figure 1

Key effectors in integrin activation and signalling pathways in T lymphocytes. After T-cell receptor (TCR)/CD3 or chemokine receptor is activated, Src kinases such as lymphocyte-specific protein tyrosine kinase (LCK) are phosphorylated and activated, leading to phosphorylation of TCR/CD3. Kinase ζ-associated protein of molecular weight 70 000 (ZAP-70) is then recruited to the TCR/CD3 complex and is phosphorylated by LCK. Activated ZAP-70 phosphorylates a number of downstream adaptors, including linker for activation of T cells (LAT) and SH2-domain-containing leucocyte protein of molecular weight 76 000 (SLP-76) (shown in yellow). Being a central scaffolding protein, SLP-76 is associated with a guanine-nucleotide exchange factor (GEF) Vav1, while VAV1 activates the GTPase Rac1, which interacts with WASP (Whiskott-Aldrich syndrome protein) and activates the ARP2/3 (actin-related protein-2/3) complex (shown in green). SLP-76 also interacts with ADAP (adhesion and degranulation promoting adapter protein), while ADAP directly binds Src kinase-associated protein of molecular weight 55 000 (SKAP-55) and VASP (WASP-family verprolin-homologous protein). SKAP-55 binds and brings RapL to membrane located GTP-Rap1, resulting in the direct interaction of RapL to lymphocyte function-associated antigen 1 (LFA-1) to increase cell adhesion (shown in red). SKAP-55 also constitutively interacts with Rap1–GTP-interacting adapter molecule (RIAM). The ability of RIAM binding to VASP and talin suggests that RIAM promotes integrin activation through effects on the actin cytoskeleton, particularly the interaction of talin with integrin cytoplasmic tails (shown in blue). Other actin-associated proteins kindlin and paxillin have also been identified to regulate integrin activation.