| First Author | Mouchemore KA | Year | 2013 |
| Journal | FEBS J | Volume | 280 |
| Issue | 21 | Pages | 5228-36 |
| PubMed ID | 23648053 | Mgi Jnum | J:216566 |
| Mgi Id | MGI:5608988 | Doi | 10.1111/febs.12316 |
| Citation | Mouchemore KA, et al. (2013) Specific inhibition of PI3K p110delta inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS J 280(21):5228-36 |
| abstractText | 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, p110delta predominates in the cell line. Treatment with p110delta-specific inhibitors demonstrates that the hematopoietically enriched isoform, p110delta, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110delta 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. |
