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

Authors

  • Kellie A. Mouchemore,

    1. School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
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  • Natalia G. Sampaio,

    1. School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
    Current affiliation:
    1. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia
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  • Michael W. Murrey,

    1. School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
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  • E. Richard Stanley,

    1. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Brian J. Lannutti,

    1. Gilead Sciences Inc., Seattle, WA, USA
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  • Fiona J. Pixley

    Corresponding author
    1. School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
    • Correspondence

      F. J. Pixley, School of Medicine and Pharmacology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia

      Tel: +618 9346 4047

      Fax: +618 9346 3469

      E-mail: fiona.pixley@uwa.edu.au

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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.

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