Journal
FEBS JOURNAL
Volume 280, Issue 21, Pages 5228-5236Publisher
WILEY-BLACKWELL
DOI: 10.1111/febs.12316
Keywords
CSF-1R; GS-1101; invasion: macrophage; PI3K p110
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Funding
- Australian National Health and Medical Research Council [535903, 427601, 535914]
- Cancer Institute of New South Wales [10/TPG/1-04]
- Sydney Catalyst Translational Research Centre [11/TRC/1-02, 10/CRF/1-07]
- Australia and New Zealand Breast Cancer Trials Group
- Australian Cancer Research Foundation
- Sydney Breast Cancer Foundation
- RT Hall Trust
- Petre Foundation
- Danish Council for Independent Research
- Human Frontier Science Program
- Bildungsministerium fur Bildung und Forschung [03Z1CN21]
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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 classIA PI3K isoforms, p110 predominates in the cell line. Treatment with p110-specific inhibitors demonstrates that the hematopoietically enriched isoform, p110, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110 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.
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