Specific inhibition of PI3K p110δ inhibits CSF‐1‐induced macrophage spreading and invasive capacity

Journal article

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.

Authors: Mouchemore, KA; Sampaio, N; Murrey, MW; Stanley, ER; Lannutti, BJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: FEBS Journal
• Volume: 280
• Issue: 21
• Pages: 5228-5236
• Publication date: 2013-06-05
• Acceptance date: 2013-04-30
• DOI: 10.1111/febs.12316
• EISSN: 1742-4658
• ISSN: 1742-464X
• Language: English
• Keywords: GS‐1101; CSF‐1R; PI3K p110δ; invasion: macrophage