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FEBS J. 2013 Nov;280(21):5228-36. doi: 10.1111/febs.12316. Epub 2013 Jun 5.

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

Author information

1
School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia.

Abstract

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.

KEYWORDS:

CSF-1R; GS-1101; PI3K p110δ; invasion: macrophage

PMID:
23648053
PMCID:
PMC3773002
DOI:
10.1111/febs.12316
[Indexed for MEDLINE]
Free PMC Article
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