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Bilancio, A. et al.

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.

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.[1]

References

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. Bilancio, A., Okkenhaug, K., Camps, M., Emery, J.L., Ruckle, T., Rommel, C., Vanhaesebroeck, B. Blood (2006) [Pubmed]

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