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P-Rex1 limits the agonist-induced internalization of GPCRs independently of its Rac-GEF activity
Baker, M. J. Hampson, E. Islam, P. Moral, R. P. Maunders, E. A. Hornigold, K. Tsonou, E. Malliri, A. Hornigold, D. C. Hubbard, R. E.
Baker, M. J.
Hampson, E.
Islam, P.
Moral, R. P.
Maunders, E. A.
Hornigold, K.
Tsonou, E.
Malliri, A.
Hornigold, D. C.
Hubbard, R. E.
Abstract
The guanine-nucleotide exchange factor (GEF) P-Rex1 mediates G protein-coupled receptor (GPCR) signaling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalization of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP, and inositol polyphosphate 4-phosphatase 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 internalization of the receptor tyrosine kinases PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalization. P-Rex1 binds G protein-coupled receptor kinase 2 (Grk2), both in vitro and in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalization of GPCRs through its interaction with Grk2 to maintain high levels of active GPCRs at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses by controlling GPCR trafficking through an adapter function as well as by mediating GPCR signaling through its Rac-GEF activity.
Authors
Baker, M. J.
Hampson, E.
Islam, P.
Moral, R. P.
Maunders, E. A.
Hornigold, K.
Tsonou, E.
Malliri, A.
Hornigold, D. C.
Hubbard, R. E.
Massey, A. J.
Welch, H. C. E.
Hampson, E.
Islam, P.
Moral, R. P.
Maunders, E. A.
Hornigold, K.
Tsonou, E.
Malliri, A.
Hornigold, D. C.
Hubbard, R. E.
Massey, A. J.
Welch, H. C. E.
Affiliation
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK; Cell Signalling Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, UK.
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Cell Signalling Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, UK.
Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Vernalis (R&D) Ltd., Granta Park, Cambridge, UK.
Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK. Electronic address: heidi.welch@babraham.ac.uk.
Description
Date
2025
Publisher
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Article
Citation
Baker MJ, Hampson E, Islam P, Moral RP, Maunders EA, Hornigold K, et al. P-Rex1 limits the agonist-induced internalization of GPCRs independently of its Rac-GEF activity. Cell reports. 2025 Oct 14;44(10):116403. PubMed PMID: 41100251. Epub 2025/10/16. eng.