Requirement for PI 3-kinase γ in macrophage migration to MCP-1 and CSF-1

• Published in: Experimental cell research Vol. 290; no. 1; pp. 120 - 131
• Main Authors: Jones, Gareth E., Prigmore, Elena, Calvez, Ronan, Hogan, Catherine, Dunn, Graham A., Hirsch, Emilio, Wymann, Matthias P., Ridley, Anne J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2003
• Subjects: Actin cytoskeleton; Actin Cytoskeleton - metabolism; Animals; Cell Membrane Structures - metabolism; Cell migration; Cell Migration Inhibition; Cell Polarity - drug effects; Cell Polarity - physiology; Cells, Cultured; Chemokine CCL2 - pharmacology; Chemokines; Chemotaxis; Chemotaxis - drug effects; Chemotaxis - physiology; Class Ib Phosphatidylinositol 3-Kinase; CSF-1; G protein-coupled receptor; GTP-Binding Proteins - metabolism; Isoenzymes - deficiency; Isoenzymes - genetics; Macrophage; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages - drug effects; Macrophages - enzymology; MCP-1; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases - deficiency; Phosphatidylinositol 3-Kinases - genetics; PI 3-kinases; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, Cell Surface - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Tyrosine kinase receptors; G protein-coupled receptor; MCP-1; Tyrosine kinase receptors; PI 3-kinases; CSF-1; Actin cytoskeleton; Chemotaxis; Chemokines; Cell migration; Macrophage
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/S0014-4827(03)00318-5

Phosphoinositide 3-kinases (PI3Ks) are important regulators of cell migration. The PI3K isoform γ is primarily expressed in haematopoietic cells, and is activated by G protein-coupled receptors (GPCRs). Here, we investigate the contribution of PI3Kγ to macrophage responses to chemoattractants, using bone marrow-derived macrophages from wild-type and PI3Kγ-null mice. We observe that early membrane ruffling induced by MCP-1, which activates a GPCR, or by CSF-1, which activates a tyrosine kinase receptor, is unaltered in PI3Kγ −/− mice, although by 30 min MCP-1-induced cell polarization was strongly reduced in PI3Kγ −/− compared to wild-type macrophages. The migration behaviour of the macrophages was analysed by time-lapse microscopy in Dunn chemotaxis chambers. PI3Kγ −/− macrophages showed reduced migration speed and translocation, and no chemotaxis to MCP-1. Interestingly, there was also a reduction in migration efficiency in PI3Kγ −/− macrophages stimulated with CSF-1 although early CSF-1R signalling was normal. These results indicate that the initial actin reorganization induced by either a GPCR or tyrosine kinase receptor agonist is not dependent on PI3Kγ, whereas PI3Kγ is needed for optimal migration of macrophages to either agonist.