%0 Journal Article
%T Pivotal Role of AKAP12 in the Regulation of Cellular Adhesion Dynamics: Control of Cytoskeletal Architecture, Cell Migration, and Mitogenic Signaling
%A Shin Akakura
%A Irwin H. Gelman
%J Journal of Signal Transduction
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/529179
%X Cellular dynamics are controlled by key signaling molecules such as cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). AKAP12/SSeCKS/Gravin (AKAP12) is a scaffold protein for PKA and PKC which controls actin-cytoskeleton reorganization in a spatiotemporal manner. AKAP12 also acts as a tumor suppressor which regulates cell-cycle progression and inhibits Src-mediated oncogenic signaling and cytoskeletal pathways. Reexpression of AKAP12 causes cell flattening, reorganization of the actin cytoskeleton, and the production of normalized focal adhesion structures. Downregulation of AKAP12 induces the formation of thickened, longitudinal stress fibers and the proliferation of adhesion complexes. AKAP12-null mouse embryonic fibroblasts exhibit hyperactivation of PKC, premature cellular senescence, and defects in cytokinesis, relating to the loss of PKC scaffolding activity by AKAP12. AKAP12-null mice exhibit increased cell senescence and increased susceptibility to carcinogen-induced oncogenesis. The paper describes the regulatory and scaffolding functions of AKAP12 and how it regulates cell adhesion, signaling, and oncogenic suppression. 1. Introduction The actin cytoskeleton plays an essential role in numerous aspects of cell biology such as cell adhesion, cell morphology, cytokinesis, and migration. Cell migration machinery is regulated by signaling intermediates that can be activated by diverse stimuli and that can exert control over a large number of downstream target molecules, all with temporal and spatial specificity [1, 2]. PKA, PKC, and C a 2 + -binding proteins are examples of cellular regulators that mediate diverse effects on cytoskeletal dynamics, cell adhesion, and cell migration [3, 4]. Control of the subcellular localization of PKA and PKC activities in a temporal manner by A-Kinase-Anchoring Proteins (AKAP) has emerged as a pivotal mechanism to control cell migration [2]. For instance, AKAP12/SSeCKS/Gravin (AKAP12) is thought to control a number of cellular events by scaffolding key signaling molecules such as cyclin D1, calmodulin, PKA, and PKC (Figure 1) [5]. Figure 1: AKAP12 binds to key signaling molecules. AKAP12 contains various demonstrated protein binding domains as well as PKC phosphorylation sites (pS) and a tyrosine phosphorylation site (pY). NLS, nuclear localization signals (at least 4 T ag motifs); CaM, calmodulin; GalTase, ¦Â1,4-galactosyltransferase; Myr, N-terminal myristoylation. SSeCKS (rodent AKAP12), the Src-Suppressed-C-Kinase-Substrate, was originally identified in a screen for genes severely downregulated by
%U http://www.hindawi.com/journals/jst/2012/529179/