Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells - PubMed (original) (raw)

Comparative Study

. 2006 Jan 15;107(2):642-50.

doi: 10.1182/blood-2005-07-3041. Epub 2005 Sep 22.

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• PMID: 16179367
• DOI: 10.1182/blood-2005-07-3041

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Comparative Study

Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells

Antonio Bilancio et al. Blood. 2006.

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Abstract

Mouse gene-targeting studies have documented a central role of the p110delta isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110delta-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110delta in BCR signaling. p110delta activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 alpha/beta (GSK3alpha/beta) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110delta catalytic activity. Resting B cells with inactive p110delta fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110delta is also critical for interleukin 4 (IL-4)-induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110delta mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110delta as a drug target in autoimmune diseases in which B cells play a crucial role.

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