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

Kellie A. Mouchemore, Natalia G. Sampaio, Michael W. Murrey, E. Richard Stanley, Brian J. Lannutti, Fiona J. Pixley

Research output: Contribution to journalArticle

21 Citations (Scopus)

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. CSF-1-induced phosphorylation of CSF-1R Y721 mediates association of PI3K to trigger PIP3 production and spreading and invasive capacity in macrophages. These activities are mediated solely by the p110™ isoform in a macrophage cell line, M-/-.WT, and in primary macrophages. GS-1101, a potent and selective p110™ inhibitor, inhibits macrophage invasion and matrix degradation.

Original languageEnglish (US)
Pages (from-to)5228-5236
Number of pages9
JournalFEBS Journal
Volume280
Issue number21
DOIs
StatePublished - Nov 2013

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Macrophage Colony-Stimulating Factor
1-Phosphatidylinositol 4-Kinase
Macrophages
Phosphatidylinositols
Phosphotransferases
Phosphorylation
Macrophage Colony-Stimulating Factor Receptors
Cells
Protein Isoforms
Tumors
Cell Line
Colony-Stimulating Factor Receptors
Bone
Association reactions
Neoplasms
Macrophage Activation
Phagocytes
Cell growth
Corrosion inhibitors
Cell Differentiation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mouchemore, K. A., Sampaio, N. G., Murrey, M. W., Stanley, E. R., Lannutti, B. J., & Pixley, F. J. (2013). Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS Journal, 280(21), 5228-5236. https://doi.org/10.1111/febs.12316

Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity. / Mouchemore, Kellie A.; Sampaio, Natalia G.; Murrey, Michael W.; Stanley, E. Richard; Lannutti, Brian J.; Pixley, Fiona J.

In: FEBS Journal, Vol. 280, No. 21, 11.2013, p. 5228-5236.

Research output: Contribution to journalArticle

Mouchemore, KA, Sampaio, NG, Murrey, MW, Stanley, ER, Lannutti, BJ & Pixley, FJ 2013, 'Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity', FEBS Journal, vol. 280, no. 21, pp. 5228-5236. https://doi.org/10.1111/febs.12316
Mouchemore KA, Sampaio NG, Murrey MW, Stanley ER, Lannutti BJ, Pixley FJ. Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity. FEBS Journal. 2013 Nov;280(21):5228-5236. https://doi.org/10.1111/febs.12316
Mouchemore, Kellie A. ; Sampaio, Natalia G. ; Murrey, Michael W. ; Stanley, E. Richard ; Lannutti, Brian J. ; Pixley, Fiona J. / Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity. In: FEBS Journal. 2013 ; Vol. 280, No. 21. pp. 5228-5236.
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AB - 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. CSF-1-induced phosphorylation of CSF-1R Y721 mediates association of PI3K to trigger PIP3 production and spreading and invasive capacity in macrophages. These activities are mediated solely by the p110™ isoform in a macrophage cell line, M-/-.WT, and in primary macrophages. GS-1101, a potent and selective p110™ inhibitor, inhibits macrophage invasion and matrix degradation.

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