Reconstruction of integrin activation

Abstract

IntroductionWhat I cannot create, I do not understand. Richard Feynman Regulation of cell adhesion through cell-matrix or cell-cell interaction is a critical step in various physiologic processes, such as cell migration and anchoring during development of the blood-forming organs, recruitment of cells into sites of inflammation, and aggregation and adhesion of platelets. Integrins are cell surface receptors composed of type I heterodimeric transmembrane proteins, formed by a combination of 18 ␣-subunits and 8 ␤-subunits. Twenty-four integrins have been identified so far. 1 In blood cells, integrins are usually in a resting (inactive) state with low affinity for their ligands; they can quickly switch to an activated, high-affinity state in response to agonists, such as proteases or adenine nucleotides, a process often referred to as inside-out activation or inside-out signaling. [1][2][3][4][5] Disruption of integrin function causes several hematologic diseases. For example, loss of integrin-␣IIb␤3 (GPIIb-IIIa), the most abundant platelet integrin, causes Glanzmann thrombasthenia, a hereditary hemorrhagic disorder. [6][7][8][9] In the early 1990s, investigators also identified Glanzmann thrombasthenia patients whose platelet ␣IIb␤3, although expressed in normal amount, cannot be activated by agonists because of mutations in the ␤3 cytoplasmic domain. 10,11 These mutations, although not fully explained until the recent understanding of talin and kindlin function in integrin regulation, provided important early insight indicating that integrins were regulated from inside-out (reviewed in the last section).Similarly, a subset of integrins, such as ␤2-integrins and ␣4-integrins, are expressed in leukocytes and mediate their adhesion to endothelium during various stages of extravasation during inflammatory responses. Loss of integrin-␤2 (CD18) expression causes leukocyte adhesion deficiency I (LAD I), a disease characterized by recurrent infections. 12 Certain patients with LAD symptoms have normal levels of ␤2-integrins combined with a bleeding diathesis. These patients' leukocytes are defective in ␤2-and ␤1-integrin activation, whereas their platelets also exhibit defects in activation of ␣IIb␤3; this variant is termed LAD III, or Lad1v. [13][14][15][16] The defective integrin activation in these LAD patients is caused by kindlin-3 mutations. [13][14][15]17 Some groups have also suggested the name of integrin activation deficiency disease for these conditions. 14 Furthermore, Kindler syndrome, a skin blistering disease, is the result of defective ␤1-integrin activation caused by kindlin-1 mutations. 18,19 As proteins involved in multiple biologic processes and located at the cell surface, integrins are also readily accessible therapeutic targets. For example, inhibitors of integrin-␣IIb␤3 are currently used in the prevention and treatment of arterial thrombosis in the acute settings of percutaneous coronary intervention. 20 Other integrin-blocking agents against ␣4 are currently used for multiple sclerosis and Croh...

Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation

“…Integrins can be found in an 'inactive' state with relatively low affinity for ECM ligands or in an 'active' conformation with high ligandbinding affinity (Calderwood, 2004a). Integrin activation (the conversion from inactive to active states) can be triggered by binding to ECM or by intracellular signaling events that culminate in the binding of the cytoskeletal adaptor protein talin to the cytoplasmic tail of the integrin b subunit Shattil et al, 2010;Ye et al, 2012). Once activated or engaged by ECM molecules, integrin receptors can cluster to form focal adhesions (FAs) Wehrle-Haller, 2012).…”

In vivo regulation of integrin turnover by outside-in activation

“…This arrangement allows integrin to exist in multiple conformations with differing affinities for its ECM ligands. In its lowest affinity state, the 'knees' are bent and the head region is closed, whereas in its highest affinity state, the entire extracellular domain is extended and the head is open; many intermediate states also exist (Campbell and Humphries, 2011;Ye et al, 2012;Zhang and Chen, 2012). Integrin activation is proposed to involve the switchblade-like extension of the extracellular homodimer that extends the ligandbinding head region away from the plasma membrane (Shattil et al, 2010;Takagi et al, 2002).…”

“…Integrin activation is proposed to involve the switchblade-like extension of the extracellular homodimer that extends the ligandbinding head region away from the plasma membrane (Shattil et al, 2010;Takagi et al, 2002). The divalent cations Mn 2+ and Mg 2+ are known to be potent activators of integrin, and induce an increase in affinity for ECM ligands across multiple integrin heterodimers (Ye et al, 2012). It is known that for at least certain integrin heterodimers, divalent cations mimic ligand binding and induce activation by inducing wholesale conformational change (Takagi et al, 2002;Ye et al, 2012).…”

“…The divalent cations Mn 2+ and Mg 2+ are known to be potent activators of integrin, and induce an increase in affinity for ECM ligands across multiple integrin heterodimers (Ye et al, 2012). It is known that for at least certain integrin heterodimers, divalent cations mimic ligand binding and induce activation by inducing wholesale conformational change (Takagi et al, 2002;Ye et al, 2012). Mn 2+ is particularly effective at activating integrins, whereas, at least in culture, Mg 2+ has been suggested to activate integrin only at very low Ca 2+ concentrations (Dransfield et al, 1992).…”

Integrin CD11c/CD18 α-Chain Phosphorylation Is Functionally Important

“…Other members include CD11a/CD18 (␣ L ␤ 2 , LFA-1), CD11b/CD18 (␣ M ␤ 2 , Mac-1), and CD11d/CD18 (␣ D ␤ 2 ). The leukocyte CD11/CD18 integrins are involved in various immunological functions, including cell adhesion, migration, and phagocytosis (2)(3)(4)(5)(6).…”