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Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110 but Not p110 Promotes Optimal Allergic Responses In Vivo¹

Khaled Ali^*, Montserrat Camps, Wayne P. Pearce^*, Hong Ji, Thomas Rückle, Nicolas Kuehn, Christian Pasquali, Christian Chabert, Christian Rommel^2, and Bart Vanhaesebroeck^3,*

^* Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London, London, United Kingdom; Geneva Research Center, Merck Serono International, Geneva, Switzerland; and Frimorfo, Fribourg, Switzerland

The leukocyte-enriched p110 and p110 isoforms of PI3K have been shown to control in vitro degranulation of mast cells induced by cross-linking of the high affinity receptor of IgE (FcRI). However, the relative contribution of these PI3K isoforms in IgE-dependent allergic responses in vivo is controversial. A side-by-side comparative analysis of the role of p110 and p110 in mast cell function, using genetic approaches and newly developed isoform-selective pharmacologic inhibitors, confirms that both PI3K isoforms play an important role in FcRI-activated mast cell degranulation in vitro. In vivo, however, only p110 was found to be required for optimal IgE/Ag-dependent hypersensitivity responses in mice. These observations identify p110 as a key therapeutic target among PI3K isoforms for allergy- and mast cell-related diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Biotechnology and Biological Science Research Council U.K. (Grant BB/C505659/1), the European Union FP6-502935, Barts and the London Charity, and the Ludwig Institute for Cancer Research.

² Current address: Intellikine, La Jolla, CA 92037.

³ Address correspondence and reprint requests to Dr. Bart Vanhaesebroeck, Centre for Cell Signaling, Institute of Cancer, Queen Mary, University of London, Sir John Vane Research Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail address: bart.vanh{at}qmul.ac.uk

⁴ Abbreviations used in this paper: GPCR, G protein-coupled receptor; BMMC, bone marrow-derived mast cell; HSA, human serum albumin; i.d., intradermal; KO, knock-out; PCA, passive cutaneous anaphylaxis; SCF, stem cell factor; WT, wild type; Tyr, tyrosine; PKB, protein kinase B.