Structural Basis of Integrin Regulation and Signaling

Abstract

Integrins are cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cellpathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 Å couple to conformational change in ligand-binding sites and are linked to changes in α and β subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics.

Structural and mechanical functions of integrins

“…extended with an open headpiece (Xiong et al 2001(Xiong et al , 2002Shimaoka et al 2003;Xiao et al 2004). At the present time, two models are proposed to describe the process of integrin activation: the 'deadbolt' model and the 'switchblade' model (Xiong et al 2003;Luo et al 2007). The 'deadbolt' model proposes that integrin activation and extension occur after ligand binding, whereas the 'switchblade' model suggests that ligand binding only occurs once the integrin heterodimer is in the active extended conformation (Takagi et al 2001;Beglova et al 2002;Shimaoka et al 2002).…”

“…The function of the cytoplasmic tails during integrin activation is to facilitate the binding of integrin adaptor proteins, such as talin and kindlin, via NxxY motifs (Calderwood et al 1999). Upon adaptor protein binding, the cytoplasmic tails separate along with the TM domains, which destabilises the tail-head interface and facilitates the 'switchblade'-like opening, causing the hybrid domain to swing out and integrin to enter the high-affinity or active conformation Vinogradova et al 2002;Xiao et al 2004;Luo et al 2007). In this 'active' extended conformation with open headpiece, integrins are able to bind extracellular ligands, which further stabilises the integrin heterodimer and eventually leads to integrin clustering, intracellular kinase recruitment and activation of downstream signalling pathways ).…”

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

“…MRNA expression was measured at 24h by RT-PCR using 18S as an internal control. PTHrP protein secretion was measured in conditioned medium at 48h using a two-site immunoradiometric assay (IRMA) and normalized for cell number integrins binds to ligands in the matrix, such as fibronectin, vitronectin, or laminin [62,63], while the cytoplasmic domains bind to proteins associated with cytoskeletal linkage and signaling [61,64]. Integrin binding to the ligands in the matrix results in integrin clustering and activation of enzymes including kinases (e.g., focal adhesion kinase (FAK)) and phosphatases (e.g., tyrosine phosphatase-α (RPTP-α)) that regulate signal transduction within the cell [50,61].…”

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

“…ICAM-1/CD54 is the major ligand of costimulatory a L b 2 integrin (CD11a/CD18), commonly known as lymphocyte function-associated antigen (LFA-1) [23,24]. The surface enhancement of ICAM-1 on endothelial, APC and B cells have pleiotropic effects in LFA-1-mediated T lymphocyte responses including T-cell homing [25], formation and stabilization of immunosynapse [26,27], T-cell memory differentiation [28], and Th1 polarization [29,30], among others.…”

“…These unconventional capabilities include [16,17,18] and direct pathogen recognition [19,20]. In this regard, a novel innate immune cell population called Interferon-producing killer dendritic cells has been recently described in mice [21,22].ICAM-1/CD54 is the major ligand of costimulatory a L b 2 integrin (CD11a/CD18), commonly known as lymphocyte function-associated antigen (LFA-1) [23,24]. The surface enhancement of ICAM-1 on endothelial, APC and B cells have pleiotropic effects in LFA-1-mediated T lymphocyte responses including T-cell homing [25], formation and stabilization of immunosynapse [26,27], T-cell memory differentiation [28], and Th1 polarization [29,30], among others.…”