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Sci. Signal., 12 April 2011
Vol. 4, Issue 168, p. ra23
[DOI: 10.1126/scisignal.2001617]


Editor's Summary

The Integrating Isoform
The class I phosphoinositide 3-kinases (PI3Ks) are implicated in processes such as growth factor signaling and inflammation. PI3K{gamma} is activated by G protein–coupled receptors (GPCRs), whereas PI3Kα and PI3K{delta} are activated by protein tyrosine kinase–coupled receptors. PI3Kβ is unusual in that it appears to respond to signals from both types of receptors, depending on the cellular context. Kulkarni et al. investigated the responses of mouse neutrophils to immune complexes of antibody and antigen, which trigger chronic inflammation in conditions such as autoimmune arthritis. Genetic and pharmacological evidence suggested that immune complexes stimulated PI3Kβ in a process involving activation of Fc{gamma}R, a tyrosine kinase–coupled low-affinity antibody receptor, and autocrine signaling by a proinflammatory lipid (LTB4) through its GPCR. Mice deficient in PI3Kβ fared better than did controls in models of arthritis and inflammatory skin disease. These data implicate PI3Kβ in the integration of signals from tyrosine kinase–coupled receptors and GPCRs—and suggest that this isoform may be an effective therapeutic target in inflammatory diseases.

Citation: S. Kulkarni, C. Sitaru, Z. Jakus, K. E. Anderson, G. Damoulakis, K. Davidson, M. Hirose, J. Juss, D. Oxley, T. A. M. Chessa, F. Ramadani, H. Guillou, A. Segonds-Pichon, A. Fritsch, G. E. Jarvis, K. Okkenhaug, R. Ludwig, D. Zillikens, A. Mocsai, B. Vanhaesebroeck, L. R. Stephens, P. T. Hawkins, PI3Kβ Plays a Critical Role in Neutrophil Activation by Immune Complexes. Sci. Signal. 4, ra23 (2011).

Read the Full Text

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Class I Phosphoinositide-3-Kinases and Src Kinases Play a Nonredundant Role in Regulation of Adhesion-Independent and -Dependent Neutrophil Reactive Oxygen Species Generation.
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Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies.
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Structural Basis for Activation and Inhibition of Class I Phosphoinositide 3-Kinases.
O. Vadas, J. E. Burke, X. Zhang, A. Berndt, and R. L. Williams (2011)
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