P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils

George Damoulakis, Laure Gambardella, Kent L. Rossman, Campbell D. Lawson, Karen E. Anderson, Yoshinori Fukui, Heidi C. Welch, Channing J. Der, Len R. Stephens, Phillip T. Hawkins

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

G-protein-coupled receptors (GPCRs) regulate the organisation of the actin cytoskeleton by activating the Rac subfamily of small GTPases. The guanine-nucleotide-exchange factor (GEF) P-Rex1 is engaged downstream of GPCRs and phosphoinositide 3-kinase (PI3K) in many cell types, and promotes tumorigenic signalling and metastasis in breast cancer and melanoma, respectively. Although P-Rex1-dependent functions have been attributed to its GEF activity towards Rac1, we show that P-Rex1 also acts as a GEF for the Rac-related GTPase RhoG, both in vitro and in GPCR-stimulated primary mouse neutrophils. Furthermore, loss of either P-Rex1 or RhoG caused equivalent reductions in GPCR-driven Rac activation and Rac-dependent NADPH oxidase activity, suggesting they both function upstream of Rac in this system. Loss of RhoG also impaired GPCR-driven recruitment of the Rac GEF DOCK2, and Factin, to the leading edge of migrating neutrophils. Taken together, our results reveal a new signalling hierarchy in which P-Rex1, acting as a GEF for RhoG, regulates Rac-dependent functions indirectly through RhoG-dependent recruitment of DOCK2. These findings thus have broad implications for our understanding of GPCR signalling to Rho GTPases and the actin cytoskeleton.

Original languageEnglish
Pages (from-to)2589-2600
Number of pages12
JournalJournal of cell science
Volume127
Issue number11
DOIs
Publication statusPublished - Jun 2014

All Science Journal Classification (ASJC) codes

  • Cell Biology

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