Beta-arrestins operate an on/off control switch for focal adhesion kinase activity

• Published in: Cellular and molecular life sciences : CMLS 2020-12, Vol.77 (24), p.5259-5279
• Main Authors: Alexander, Revu Ann, Lot, Isaure, Saha, Kusumika, Abadie, Guillaume, Lambert, Mireille, Decosta, Eleonore, Kobayashi, Hiroyuki, Beautrait, Alexandre, Borrull, Aurélie, Asnacios, Atef, Bouvier, Michel, Scott, Mark G. H., Marullo, Stefano, Enslen, Hervé
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex 2 - genetics; Adhesion; Angiotensin AT1 receptors; Animals; Arrestin; beta-Arrestins - genetics; Biochemistry; Biological activity; Biomedical and Life Sciences; Biomedicine; Cancer; Cell activation; Cell Biology; Cell Membrane - genetics; Cellular Biology; Depletion; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - genetics; Focal Adhesion Protein-Tyrosine Kinases - metabolism; G protein-coupled receptors; GTP-Binding Proteins - genetics; HEK293 Cells; Humans; Kinases; Life Sciences; Membranes; Mice; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Original; Original Article; Phosphorylation - drug effects; Protein Binding - genetics; Protein Domains - genetics; Proteins; Receptor, Angiotensin, Type 1 - genetics; Receptors; Receptors, G-Protein-Coupled - genetics; Scaffolding; Stimulation; Translocation; Vasopressin; Vasopressins - pharmacology
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03471-5

Focal adhesion kinase (FAK) regulates key biological processes downstream of G protein-coupled receptors (GPCRs) in normal and cancer cells, but the modes of kinase activation by these receptors remain unclear. We report that after GPCR stimulation, FAK activation is controlled by a sequence of events depending on the scaffolding proteins β-arrestins and G proteins. Depletion of β-arrestins results in a marked increase in FAK autophosphorylation and focal adhesion number. We demonstrate that β-arrestins interact directly with FAK and inhibit its autophosphorylation in resting cells. Both FAK–β-arrestin interaction and FAK inhibition require the FERM domain of FAK. Following the stimulation of the angiotensin receptor AT 1A R and subsequent translocation of the FAK–β-arrestin complex to the plasma membrane, β-arrestin interaction with the adaptor AP-2 releases inactive FAK from the inhibitory complex, allowing its activation by receptor-stimulated G proteins and activation of downstream FAK effectors. Release and activation of FAK in response to angiotensin are prevented by an AP-2-binding deficient β-arrestin and by a specific inhibitor of β-arrestin/AP-2 interaction; this inhibitor also prevents FAK activation in response to vasopressin. This previously unrecognized mechanism of FAK regulation involving a dual role of β-arrestins, which inhibit FAK in resting cells while driving its activation at the plasma membrane by GPCR-stimulated G proteins, opens new potential therapeutic perspectives in cancers with up-regulated FAK.