Cytoplasmic salt bridge formation in integrin αvß3 stabilizes its inactive state affecting integrin-mediated cell biological effects

Martina A. Müller, Leonora Brunie, Anne Sophie Bächer, Horst Kessler, Kay Eberhard Gottschalk, Ute Reuning

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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 ß-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 α/ß-membrane-proximal 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 αvß3 by mutually exchanging the salt bridge forming amino acid residues on each chain (αvR995D and ß3D723R). 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 αvß3-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.

Original languageEnglish
Pages (from-to)2493-2503
Number of pages11
JournalCellular Signalling
Volume26
Issue number11
DOIs
StatePublished - Nov 2014

Keywords

  • Cytoplasmic salt bridge
  • Integrin activation
  • Integrin signaling
  • Integrin αvß3
  • Ovarian cancer

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