FcgammaRIIb modulation of surface immunoglobulin-induced Akt activation in murine B cells.
We examined activation of the serine/threonine kinase Akt in the murine B cell line A20. Akt is activated in a phosphoinositide 3-kinase (PtdIns 3-kinase)-dependent manner upon stimulation of the antigen receptor, surface immunoglobulin (sIg). In contrast, Akt induction is reduced upon co-clustering of sIg with the B cell IgG receptor, FcgammaRIIb. Co-clustering of sIg-FcgammaRIIb transmits a dominant negative signal and is associated with reduced accumulation of the PtdIns 3-kinase product phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P3), known to be a potent activator of Akt. PtdIns 3-kinase is activated to the same extent with and without FcgammaRIIb co-ligation, indicating conditions supporting the generation of PtdIns 3,4,5-P3. We hypothesized that the decreased Akt activity arises from the consumption of PtdIns 3,4,5-P3 by the inositol-5-phosphatase Src homology 2-containing inositol 5-phosphatase (SHIP), which has been shown by us to be tyrosine-phosphorylated and associated with FcgammaRIIb when the latter is co-ligated. In direct support of this hypothesis, we report here that Akt induction is greatly reduced in fibroblasts expressing catalytically active but not inactive SHIP. Likewise, the reduction in Akt activity upon sIg-FcgammaRIIb co-clustering is absent from avian B cells lacking expression of SHIP. These findings indicate that SHIP acts as a negative regulator of Akt activation.
Jacob
A
A
Department of Microbiology and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Cooney
D
D
Tridandapani
S
S
Kelley
T
T
Coggeshall
K M
KM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D015544:Inositol 1,4,5-Trisphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt