The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells

M. Javad Aman, Thomas D. Lamkin, Hidetaka Okada, Tomohiro Kurosaki, Kodimangalam S. Ravichandran

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

The serine-threonine kinase Akt/PKB is activated downstream of phosphatidylinositol 3-kinase in response to several growth factor stimuli and has been implicated in the promotion of cell survival. Although both phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) have been implicated in the regulation of Akt activity in vitro, the relative roles of these two phospholipids in vivo are not well understood. Co-ligation of the B cell receptor (BCR) and the inhibitory F(c)γRIIB1 on B cells results in the recruitment of the 5'- inositol phosphatase SHIP to the signaling complex. Since SHIP is known to cleave PIP3 to generate PI 3,4-P2 both in vivo and in vitro, and Akt activity has been reported to be regulated by either PIP3 or PI 3,4-P3, we hypothesized that recruitment of SHIP through F(c)γRIIB1 co-cross-linking to the BCR in B cells might regulate Akt activity. The nature of this regulation, positive or negative, might also reveal the relative contribution of PIP3 and PI 3,4-P2 to Akt activation in vivo. Here we report that Akt is activated by stimulation through the BCR in a phosphatidylinositol 3-kinase- dependent manner and that this activation is inhibited by co-cross-linking of the BCR to F(c)γRIIB1. Using mutants of F(c)γRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within F(c)γRIIB1 as well as SHIP. The SHIP-dependent inhibition of Akt activation also suggests that PIP3 plays a greater role in Akt activation than PI 3,4-P2 in vivo.

Original languageEnglish
Pages (from-to)33922-33928
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number51
DOIs
StatePublished - Dec 18 1998

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