title: PDK1 controls upstream PI3K expression and PIP3 generation.
abstract: The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.
authors.affiliation: Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Dieterle
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Böhler
authors.affiliation: Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Keppeler
authors.affiliation: Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Alers
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Berleth
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Drießen
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hieke
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pietkiewicz
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: A S
authors.initials: AS
authors.lastname: Löffler
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Peter
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: A
authors.initials: A
authors.lastname: Gray
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: N R
authors.initials: NR
authors.lastname: Leslie
authors.affiliation: Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Institute of Cellular and Molecular Immunology, University Hospital Göttingen, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Engelke
authors.affiliation: Institute of Cellular and Molecular Immunology, University Hospital Göttingen, Göttingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wienands
authors.affiliation: Department of Medical Genetics, MFT Services, University Hospital Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bonin
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wesselborg
authors.affiliation: Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Stork
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002645:Chickens; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D058570:TOR Serine-Threonine Kinases; C000631429:PDK1 protein, human