Integrin and CD3/TCR activation are regulated by the scaffold protein AKAP450

Abstract

IntroductionDuring the process of antigen recognition by T cells, structural and spatial changes take place at the immune synapse (IS) formed at the contact with antigen-presenting cells (APCs), involving various recognition and signaling molecules as well as cytoskeletal components. In T cells, the IS contains a central supramolecular activation cluster (c-SMAC), which includes the T-cell receptor (TCR)/CD3 complex and various costimulatory receptors, and a peripheral ring (p-SMAC) where molecules, such as lymphocyte functionassociated antigen 1 (LFA-1) and talin, localize. [1][2][3] The formation of the IS is associated with a substantial remodeling of the actin and tubulin cytoskeleton. 4,5 An early event on antigen recognition is the translocation of the centrosome, or microtubule-organizing center (MTOC), and the associated Golgi apparatus (GA) and secretory vesicles toward the nascent IS, bringing them in close apposition with the APCs. 6 This process provides the basis for polarized secretion of various molecules by the T cell, thus favoring controlled communication with the APCs. 7,8 Moreover, during asymmetric T lymphocyte division, stable orientation of original MTOC is essential to initiate differentiation associated with the adaptive immune responses of T cells. 9 The physical proximity of the MTOC and GA in mammalian cells is accompanied by a functional link between these organelles. The Golgi protein Golgi Matrix 130 (GM130) has recently been implicated in the regulation of MTOC morphology and function, 10,11 and Golgi Reassembly Stacking protein 65 (GRASP65) is another Golgi-associated protein required for MTOC/GA remodeling and positioning. 12 The scaffolding protein CG-NAP (centrosome and Golgi localized protein kinase N-associated protein), also known as A-kinase anchoring protein-9 (AKAP9), AKAP450, or AKAP350, is found at the MTOC in most cells but is not restricted to this location. 13,14 This molecule is a member of the AKAP (A-kinase anchoring proteins) family and recruits numerous proteins involved in signal transduction. In addition to protein kinases, such as PKA, protein kinase N, or protein kinase C-⑀ (PKC-⑀), AKAP450 also anchors phosphatases, including protein phosphatase 1 (PP1) and PP2A. 13,15,16 Specific displacement of endogenous AKAP450 by expression of the AKAP450 C-terminus, which contains the MTOC-targeting domain but not its coiled-coil domains or binding sites for signaling molecules, disrupts centrosomal function and induces cell-cycle arrest at G 1 in HeLa cells, showing defects in cytokinesis. 17 In addition, Ran-GTP, involved in nuclear import and export proteins and microtubule nucleation, associates with AKAP450 at the MTOC. 18 AKAP450 is also a component of the LFA-1-induced signaling complex involved in T-cell migration 19 ; integrins, particularly LFA-1, are critical for leukocyte migration and for the correct formation of the IS. 20 Furthermore, AKAP450 interacts with the dynein/dynactin complex, and this may be involved in the binding of the GA to the MTOC. ...

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