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First published online 25 November 2008
doi: 10.1242/jcs.032763

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Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages

Evangelia A. Papakonstanti^1,2,*, Olivier Zwaenepoel², Antonio Bilancio^1,, Emily Burns¹, Gemma E. Nock¹, Benjamin Houseman³, Kevan Shokat³, Anne J. Ridley⁴ and Bart Vanhaesebroeck^1,

¹ Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK
² Department of Biochemistry, School of Medicine, University of Crete, Vassilika Vouton, GR-71110 Heraklion, Greece
³ Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA
⁴ Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK

Author for correspondence (e-mail: bart.vanh{at}qmul.ac.uk)

Accepted 11 September 2008

The class IA isoforms of phosphoinositide 3-kinase (p110, p110β and p110) often have non-redundant functions in a given cell type. However, for reasons that are unclear, the role of a specific PI3K isoform can vary between cell types. Here, we compare the relative contributions of PI3K isoforms in primary and immortalised macrophages. In primary macrophages stimulated with the tyrosine kinase ligand colony-stimulating factor 1 (CSF1), all class IA PI3K isoforms participate in the regulation of Rac1, whereas p110 selectively controls the activities of Akt, RhoA and PTEN, in addition to controlling proliferation and chemotaxis. The prominent role of p110 in these cells correlates with it being the main PI3K isoform that is recruited to the activated CSF1 receptor (CSF1R). In immortalised BAC1.2F5 macrophages, however, the CSF1R also engages p110, which takes up a more prominent role in CSF1R signalling, in processes including Akt phosphorylation and regulation of DNA synthesis. Cell migration, however, remains dependent mainly on p110. In other immortalised macrophage cell lines, such as IC-21 and J774.2, p110 also becomes more prominently involved in CSF1-induced Akt phosphorylation, at the expense of p110.These data show that PI3K isoforms can be differentially regulated in distinct cellular contexts, with the dominant role of the p110 isoform in Akt phosphorylation and proliferation being lost upon cell immortalisation. These findings suggest that p110-selective PI3K inhibitors may be more effective in inflammation than in cancer.

Key words: PI3K, Lipid kinase, Signalling, Isoforms, RhoA, Macrophage, Redundancy

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