Journal
CELLULAR SIGNALLING
Volume 26, Issue 11, Pages 2493-2503Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.07.013
Keywords
Integrin alpha v beta 3; Integrin activation; Integrin signaling; Cytoplasmic salt bridge; Ovarian cancer
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [KE 147/39-2, RE 1156/5-1]
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Heterodimeric integrin receptors are mediators of cell adhesion, motility, invasion, proliferation, and survival. By this, they are crucially involved in (tumor) cell biological behavior. Integrins trigger signals bidirectionally across cell membranes: by outside-in, following binding of protein ligands of the extracellular matrix, and by inside-out, where proteins are recruited to g-integrin cytoplasmic tails resulting in conformational changes leading to increased integrin binding affinity and integrin activation. Computational modeling and experimental/mutational approaches imply that associations of integrin transmembrane domains stabilize the low-affinity integrin state. Moreover, a cytoplasmic interchain salt bridge is discussed to contribute to a tight clasp of the alpha/beta-membraneproximal regions; however, its existence and physiological relevance for integrin activation are still a controversial issue. In order to further elucidate the functional role of salt bridge formation, we designed mutants of the tumor biologically relevant integrin alpha v beta 3 by mutually exchanging the salt bridge forming amino acid residues on each chain (alpha v(R995D) and beta 3(D723R)). Following transfection of human ovarian cancer cells with different combinations of wild type and mutated integrin chains, we showed that loss of salt bridge formation strengthened alpha v beta 3-mediated adhesion to vitronectin, provoked recruitment of cytoskeletal proteins, such as talin, and induced integrin signaling, ultimately resulting in enhanced cell migration, proliferation, and activation of integrin-related signaling molecules. These data support the notion of a functional relevance of integrin cytoplasmic salt bridge disruption during integrin activation. (C) 2014 Elsevier Inc. All rights reserved.
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