title: Regulation of diacylglycerol kinase alpha by phosphoinositide 3-kinase lipid products.
abstract: Diacylglycerol kinase alpha (DAGK alpha), like all type I DAGKs, has calcium regulatory motifs that act as negative regulators of enzyme activity and localization. Accordingly, DAGK alpha is activated by phospholipase C-coupled receptors in a calcium-dependent manner. One of the first functions attributed to DAGK alpha in lymphocytes was that of regulating interleukin 2-induced cell cycle entry. Interleukin-2 nonetheless exerts its action in the absence of cytosolic calcium increase. We have studied alternative receptor-derived signals to explain calcium-independent DAGK alpha activation, and show that DAGK alpha is stimulated by Src-like kinase-dependent phosphoinositide 3 kinase (PI3K) activation in lymphocytes. Our results demonstrate that, in vivo, the increase in cellular levels of PI3K products is sufficient to induce DAGK alpha activation, allowing DAGK alpha relocation to the intact lymphocyte plasma membrane. This activation is isoform-specific, because other type I DAGKs are not subject to this type of regulation. These studies are the first to describe a pathway in which, in the absence of receptor-regulated calcium increase, DAGK alpha activation and membrane localization is a direct consequence of PI3K activation.
authors.affiliation: Department of Immunology and Oncology, National Center for Biotechnology, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Ciprés
authors.forename: Silvia
authors.initials: S
authors.lastname: Carrasco
authors.forename: Ernesto
authors.initials: E
authors.lastname: Merino
authors.forename: Ernesto
authors.initials: E
authors.lastname: Díaz
authors.forename: U Murali
authors.initials: UM
authors.lastname: Krishna
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.forename: Isabel
authors.initials: I
authors.lastname: Mérida
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D007376:Interleukin-2; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D019852:Diacylglycerol Kinase