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Colony stimulating factor-1 (CSF-1) stimulates mononuclear phagocytic cell survival, growth and differentiation into macrophages through activation and autophosphorylation of the CSF-1 receptor (CSF-1R). We have previously demonstrated that CSF-1-induced phosphorylation of Y721 (pY721) in the receptor kinase insert triggers its association with the p85 regulatory subunit of phosphoinositide 3'-kinase (PI3K). Binding of p85 PI3K to the CSF-1R pY721 motif activates the associated p110 PI3K catalytic subunit and stimulates spreading and motility in macrophages and enhancement of tumor cell invasion. Here we show that pY721-based signaling is necessary for CSF-1-stimulated PtdIns(3,4,5)P production. While primary bone marrow-derived macrophages and the immortalized bone marrow-derived macrophage cell line M-/-.WT express all three class IA PI3K isoforms, p110δ predominates in the cell line. Treatment with p110δ-specific inhibitors demonstrates that the hematopoietically enriched isoform, p110δ, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110δ inhibitor, may have therapeutic potential by targeting the infiltrative capacity of tumor-associated macrophages that is critical for their enhancement of tumor invasion and metastasis.

Original publication

DOI

10.1111/febs.12316

Type

Journal article

Journal

FEBS J

Publication Date

11/2013

Volume

280

Pages

5228 - 5236

Keywords

CSF-1R, GS-1101, PI3K p110δ, invasion: macrophage, Animals, Blotting, Western, Bone Marrow, Cell Adhesion, Cell Movement, Cell Proliferation, Enzyme-Linked Immunosorbent Assay, Humans, Macrophage Colony-Stimulating Factor, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Purines, Quinazolinones, Receptor, Macrophage Colony-Stimulating Factor