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J Biol Chem, Vol. 273, Issue 51, 33922-33928, December 18, 1998

The Inositol Phosphatase SHIP Inhibits Akt/PKB Activation in B Cells

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

From the  Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908 and the  Department of Molecular Genetics, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Japan

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_cRIIB1 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-P₂, we hypothesized that recruitment of SHIP through F_cRIIB1 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_cRIIB1. Using mutants of F_cRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within F_cRIIB1 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.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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