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

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    A study directed by Hervé Enslen, team Stefano Marullo

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

    The focal adhesion kinase (FAK), an essential enzyme regulating cell physiology, is upregulated in many cancers. Several pathways contribute to activate FAK, including signaling by G Protein Coupled-Receptors (GPCR). In an article published in Cellular and Molecular Life Sciences, the group of Hervé Enslen (Signaling of Receptors and Molecular Scaffolding Team, EMD Department) discovered that β-arrestins, which are scaffolding proteins participating in GPCR signaling and regulation, bind to FAK and maintain the kinase in an inactive state. Recruitment of the FAK/β-arrestin complex to ligand-activated GPCRs releases FAK from this constitutive inhibition and allows its activation.

     

    The non-receptor tyrosine kinase FAK (Focal Adhesion Kinase) controls cell adhesion and Focal Adhesion turnover, cell polarity, motility, proliferation and survival. Increased FAK expression and uncontrolled activation in tumors promotes cancer progression and metastasis formation. Inhibitors of FAK kinase activity are currently under investigation in phase I-II clinical trials for various cancers.

    FAK is activated downstream of integrins, receptor tyrosine kinases and G-protein-coupled receptors (GPCRs). So far, however, the molecular mechanisms leading to FAK activation downstream of stimulated GPCRs have remained elusive. β-arrestin 1 and 2 (β-arr1 and β-arr2) are ubiquitous protein scaffolds that were originally identified as negative regulators of GPCR function. They also control multiple signaling cascades downstream of GPCRs.

    This work shows that in non-stimulated cells β-arr inhibits FAK catalytic activity through a direct interaction with its N-terminal domain. Under basal conditions, intra-molecular contacts between the FERM (included in the N-terminal domain) and the catalytic domains maintain FAK inactive. β-arrs would stabilize this interaction and prevent FAK activation. GPCR-dependent activation of FAK is also controlled by β-arrs. The β-arr/FAK complex is recruited to the plasma membrane by stimulated receptors, driving β-arr interaction in clathrin coated pits with the adaptor protein AP-2. This contact releases FAK from β-arrs and enables kinase activation by neighbouring receptor-stimulated G proteins. Subsequently, activated FAK accumulates at Focal Adhesions and enhances their number. Release and activation of FAK in response to GPCR stimulation, are prevented by Barbadin a specific inhibitor of β-arrestin/AP-2 interaction. β-arrs thus operate an on/off switch resulting in the localized control of FAK activity. Since FAK overexpression and activation play a critical role in tumour progression and metastasis formation, FAK regulation via β-arrs likely has an important impact on cancer development.

     

    Figure legend: Under basal conditions, both β-arr1 and β-arr2 form molecular complexes with a pool of inactive non-autophosphorylated FAK in the cytoplasm, maintaining the kinase inactive and negatively regulating both the amount of activated FAK in Focal Adhesions and Focal Adhesion number. Agonist (A)-mediated GPCR activation triggers G-protein activation (illustrated by GDP to GTP exchange); phosphorylation of the receptors (P) by specific kinases (GRKs, not shown) promotes the recruitment of the β-arr-FAK complexes. β-arr interaction with AP-2 results in the release of FAK from its complex with β-arr, which relieves the inhibition exerted by β-arr on FAK, allowing its activation by G proteins and increased activated FAK at Focal Adhesion and Focal Adhesion number. 

    This figure is reproduced from: Alexander RA et al, Beta-arrestins operate an on/off control switch for focal adhesion kinase activity. Cell Mol Life Sci. Ahead of print doi:10.1007/s00018-020-03471-5.

     

    Reference

    Alexander RA, Lot I, Saha K, Abadie G, Lambert M, Decosta E, Kobayashi H, Beautrait A, Borrull A, Asnacios A, Bouvier M, Scott MGH, Marullo S, Enslen H (2020) Beta-arrestins operate an on/off control switch for focal adhesion kinase activity. Cell Mol Life Sci. Online ahead of print. doi:10.1007/s00018-020-03471-5.

     

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