Frontline: The p85α isoform of phosphoinositide 3-kinase is essential for a subset of B cell receptor-initiated signaling responses

Abstract

Phosphoinositide 3-kinase (PI3K) is a ubiquitously expressed signaling enzyme that plays an integral role in development and activation of B cells. B cell receptor (BCR)-driven proliferation is completely blocked either in cells lacking the p85α regulatory isoform of PI3K or in wild-type cells treated with pharmacological PI3K inhibitors. However, the contribution of p85α to early signaling events has not been fully investigated. Here we show that B cells lacking p85α have signaling impairments that are both quantitatively and qualitatively different from those in cells treated with PI3K inhibitors. Loss of p85α results in partial reductions in Ca2+ mobilization and IκB phosphorylation, whereas ERK phosphorylation is not diminished. Moreover, although Akt phosphorylation is partially reduced, phosphorylation of several proteins downstream of Akt is preserved. These partial impairments suggest that there are other routes to PI3K activation in B cells apart from p85α-associated catalytic subunits. Notably, addition of phorbol ester restores BCR-mediated proliferation in p85α -deficient cells but not wild-type cells treated with PI3K inhibitors. These findings suggest that the primary BCR signaling defect in B cells lacking p85α is a failure to activate diacylglycerol-regulated signaling enzymes, most likely protein kinase C. © 2004 Wiley-VCH Verlag GmbH & Co. KGaA.