Journal
JOURNAL OF CELL SCIENCE
Volume 127, Issue 11, Pages 2589-2600Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.153049
Keywords
Cell signalling; Cell migration; NADPH oxidase; Neutrophil; Rho GEF; Small GTPase
Categories
Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J004456/1, BB/1008489/1]
- British Lung Foundation [P05/1]
- BBSRC [BB/I008489/1, BBS/E/B/000C0411, BBS/E/B/0000H183] Funding Source: UKRI
- MRC [G120/825] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0411, C20177, BB/I008489/1, BBS/E/B/0000H183] Funding Source: researchfish
- Medical Research Council [G120/825] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [25251015, 24111001, 24111007] Funding Source: KAKEN
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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.
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