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

Revu Ann Alexander1, Isaure Lot1, Kusumika Saha1

  • 1Institut Cochin, Inserm U 1016, CNRS UMR8104, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Cellular and Molecular Life Sciences : CMLS
|February 11, 2020
PubMed

Insights

G protein-coupled receptors (GPCRs) activate focal adhesion kinase (FAK) through a novel mechanism involving β-arrestins. β-arrestins initially inhibit FAK, then facilitate its activation by G proteins at the plasma membrane.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Cancer research

Background:

  • Focal adhesion kinase (FAK) is crucial for cellular processes regulated by G protein-coupled receptors (GPCRs).
  • The precise mechanisms of FAK activation by GPCRs are not fully understood.
  • FAK plays significant roles in both normal cellular functions and cancer progression.

Purpose of the Study:

  • To elucidate the role of β-arrestins and G proteins in GPCR-mediated FAK activation.
  • To investigate the sequential events controlling FAK activation downstream of GPCRs.
  • To identify potential therapeutic targets for FAK-related pathologies, particularly in cancer.

Main Methods:

  • Studied FAK activation in response to GPCR stimulation (e.g., angiotensin receptor AT1AR).
  • Utilized β-arrestin depletion and specific inhibitors to dissect signaling pathways.
  • Investigated protein-protein interactions using techniques like co-immunoprecipitation.
  • Examined the role of FAK's FERM domain and β-arrestin/AP-2 interactions.

Main Results:

  • β-arrestins directly bind to and inhibit FAK in resting cells, requiring FAK's FERM domain.
  • GPCR stimulation leads to FAK-β-arrestin complex translocation to the plasma membrane.
  • β-arrestin interaction with AP-2 releases FAK, enabling G protein-mediated activation.
  • Inhibiting β-arrestin/AP-2 interaction blocks FAK activation by angiotensin and vasopressin.

Conclusions:

  • A novel, dual role for β-arrestins in FAK regulation has been identified: initial inhibition followed by facilitation of G protein-dependent activation.
  • This mechanism highlights a previously unrecognized pathway for GPCR-controlled FAK signaling.
  • Understanding this pathway offers new therapeutic strategies for cancers characterized by elevated FAK activity.
Keywords:
AP-2Beta-arrestinFAKG proteinsG-protein-coupled receptorsβ-Arrestin

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