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Free keywords:
Animals; Bone Marrow Cells/cytology/physiology; Cells, Cultured; Enzyme Activation; Immunoglobulin E/pharmacology; Interleukin-2/secretion; Isoenzymes/genetics/metabolism Mast Cells/cytology/drug effects/physiology; Mice; Mice, Knockout; Phorbol Esters/pharmacology; Phosphorylation; Protein Kinase C/genetics/metabolism; Protein-Serine-Threonine Kinases/genetics/metabolism; Proto-Oncogene Proteins/genetics/metabolism; Receptors, IgE/metabolism; Research Support, U.S. Gov't, P.H.S.; Serine/metabolism
Abstract:
Akt (= protein kinase B), a subfamily of the AGC serine/threonine kinases, plays critical roles in survival, proliferation, glucose metabolism, and other cellular functions. Akt activation requires the recruitment of the enzyme to the plasma membrane by interacting with membrane-bound lipid products of phosphatidylinositol 3-kinase. Membrane-bound Akt is then phosphorylated at two sites for its full activation; Thr-308 in the activation loop of the kinase domain is phosphorylated by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser-473 in the C-terminal hydrophobic motif by a putative kinase PDK2. The identity of PDK2 has been elusive. Here we present evidence that conventional isoforms of protein kinase C (PKC), particularly PKCbetaII, can regulate Akt activity by directly phosphorylating Ser-473 in vitro and in IgE/antigen-stimulated mast cells. By contrast, PKCbeta is not required for Ser-473 phosphorylation in mast cells stimulated with stem cell factor or interleukin-3, in serum-stimulated fibroblasts, or in antigen receptor-stimulated T or B lymphocytes. Therefore, PKCbetaII appears to work as a cell type- and stimulus-specific PDK2.
