P-Rex1 Limits the Agonist-Induced Internalisation of GPCRs Independently of its Rac-GEF Activity

  1. Martin J. Baker
  2. Elizabeth Hampson
  3. Priota Islam
  4. Ruben Pelaez Moral
  5. Eve A. Maunders
  6. Kirsti Hornigold
  7. Elpida Tsonou
  8. David C. Hornigold
  9. Roderick E. Hubbard
  10. Andrew J. Massey
  11. Heidi C. E. Welch
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Abstract

The Rac-GEF P-Rex1 mediates GPCR signalling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalisation of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP and IP4P domains. P-Rex1 also limits the agonist-induced trafficking of CXCR4, PAR4, and GLP1R, but does not control steady-state GPCR levels, nor the agonist-induced internalisation of the RTKs PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalisation. P-Rex1 binds Grk2, bothin vitroand in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalisation of GPCRs through its interaction with Grk2 to maintain high levels of active GPCR at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses, by controlling GPCR trafficking through an adaptor function as well as by mediating GPCR signalling through its Rac-GEF activity.

Highlights

  • P-Rex1 controls GPCR trafficking, independently of its Rac-GEF activity

  • P-Rex1 limits the agonist-induced internalisation of S1PR1, CXCR4, PAR4 and GLP1R

  • P-Rex1 does not control steady-state GPCR levels, or PDGFR and EGFR trafficking

  • P-Rex1 binds Grk2 and inhibits the phosphorylation required for GPCR internalisation

eTOC blurb

P-Rex1 activates Rac downstream of GPCRs to regulate processes ranging from innate immunity to neuronal plasticity, its deregulation contributing to cancer. Here, Baker et al. show that P-Rex1 also controls GPCR trafficking, limiting agonist-induced GPCR internalisation through an adaptor function. Thus, P-Rex1 promotes GPCR responses in a dual manner.

Graphical Abstract

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