Interactome mapping of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor-1 as a new glycogen synthase kinase-3 interactor.
The phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) pathway plays pivotal roles in cell survival, growth, and proliferation downstream of growth factors. Its perturbations are associated with cancer progression, type 2 diabetes, and neurological disorders. To better understand the mechanisms of action and regulation of this pathway, we initiated a large scale yeast two-hybrid screen for 33 components of the PI3K-mTOR pathway. Identification of 67 new interactions was followed by validation by co-affinity purification and exhaustive literature curation of existing information. We provide a nearly complete, functionally annotated interactome of 802 interactions for the PI3K-mTOR pathway. Our screen revealed a predominant place for glycogen synthase kinase-3 (GSK3) A and B and the AMP-activated protein kinase. In particular, we identified the deformed epidermal autoregulatory factor-1 (DEAF1) transcription factor as an interactor and in vitro substrate of GSK3A and GSK3B. Moreover, GSK3 inhibitors increased DEAF1 transcriptional activity on the 5-HT1A serotonin receptor promoter. We propose that DEAF1 may represent a therapeutic target of lithium and other GSK3 inhibitors used in bipolar disease and depression.
Pilot-Storck
Fanny
F
UMR5239 Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure de Lyon, Lyon, France.
Chopin
Emilie
E
Rual
Jean-François
JF
Baudot
Anais
A
Dobrokhotov
Pavel
P
Robinson-Rechavi
Marc
M
Brun
Christine
C
Cusick
Michael E
ME
Hill
David E
DE
Schaeffer
Laurent
L
Vidal
Marc
M
Goillot
Evelyne
E
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping / Q000379:methods*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; D044282:Receptor, Serotonin, 5-HT1A; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C116013:DEAF1 protein, human; C546842:MTOR protein, human; C000605506:GSK3B protein, human; C448021:glycogen synthase kinase 3 alpha