Abstract
Cell migration towards a chemotactic stimulus relies on the re-arrangement of the cytoskeleton, which is triggered by activation of small G proteins RhoA, Rac1 and Cdc42, and leads to formation of lamellopodia and actin polymerisation amongst other effects. Here we show that Rac1 is important for CXCR4 induced chemotaxis but not for CCR1/CCR5 induced chemotaxis. For CXCL12-induced migration via CXCR4, breast cancer MCF-7 cells are reliant on Rac1, similarly to THP-1 monocytes and Jurkat T-cells. For CCL3-induced migration via CCR1 and/or CCR5, Rac1 signalling does not regulate cell migration in either suspension or adherent cells. We have confirmed the involvement of Rac1 with the use of a specific Rac1 blocking peptide. We also used a Rac1 inhibitor EHT 1864 and a Rac1-GEF inhibitor NSC23766 to probe the importance of Rac1 in chemotaxis. Both inhibitors did not block CCL3-induced chemotaxis, but they were able to block CXCL12-induced chemotaxis. This confirms that Rac1 activation is not essential for CCL3-induced migration, however NSC23766 might have secondary effects on CXCR4. This small molecule exhibits agonistic features in internalisation and cAMP assays, whereas it acts as an antagonist for CXCR4 in migration and calcium release assays. Our findings strongly suggest that Rac1 activation is not necessary for CCL3 signalling, and reveal that NSC23766 could be a novel CXCR4 receptor ligand.
Original language | English |
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Pages (from-to) | 88–96 |
Number of pages | 9 |
Journal | Cellular Signalling |
Volume | 42 |
Early online date | 16 Oct 2017 |
DOIs | |
Publication status | Published - Jan 2018 |
Keywords
- Chemokine receptor
- Chemotaxis
- Antagonist
- Rac1
- Ligand bias
Profiles
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Andrew Beekman
- School of Chemistry, Pharmacy and Pharmacology - Associate Professor in Medicinal Chemistry
Person: Academic, Teaching & Research
-
Leanne Stokes
- School of Chemistry, Pharmacy and Pharmacology - Associate Professor in Pharmacology
- Molecular and Tissue Pharmacology - Member
Person: Research Group Member, Academic, Teaching & Research