title: The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells.
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 FcgammaRIIB1 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 FcgammaRIIB1 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 FcgammaRIIB1. Using mutants of FcgammaRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within FcgammaRIIB1 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.
authors.affiliation: Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Aman
authors.forename: T D
authors.initials: TD
authors.lastname: Lamkin
authors.forename: H
authors.initials: H
authors.lastname: Okada
authors.forename: T
authors.initials: T
authors.lastname: Kurosaki
authors.forename: K S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D003432:Cross-Linking Reagents; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D003432:Cross-Linking Reagents; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases