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

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 recept...

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Bibliographic Details
Published in:The FEBS journal 2013-11, Vol.280 (21), p.5228-5236
Main Authors: Mouchemore, Kellie A, Sampaio, Natalia G, Murrey, Michael W, Stanley, E. Richard, Lannutti, Brian J, Pixley, Fiona J
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Bone Marrow - drug effects
Bone Marrow - metabolism
Cell Adhesion
cell invasion
Cell Movement
Cell Proliferation
cell viability
CSF‐1R
Enzyme-Linked Immunosorbent Assay
GS‐1101
Humans
invasion: macrophage
macrophage colony-stimulating factor
Macrophage Colony-Stimulating Factor - antagonists & inhibitors
Macrophage Colony-Stimulating Factor - metabolism
macrophages
Macrophages - cytology
Macrophages - drug effects
Macrophages - metabolism
metastasis
Mice
Mice, Inbred C57BL
Mice, Knockout
neoplasm cells
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Phosphatidylinositol Phosphates - metabolism
phosphorylation
PI3K p110δ
protein subunits
Purines - pharmacology
Quinazolinones - pharmacology
Receptor, Macrophage Colony-Stimulating Factor - metabolism
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Summary: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.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.12316