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.
Mesh Terms:
Animals, Cell Line, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Promoter Regions, Genetic, Protein Interaction Mapping, Protein-Serine-Threonine Kinases, Proteome, Receptor, Serotonin, 5-HT1A, Recombinant Fusion Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Two-Hybrid System Techniques
Mol. Cell Proteomics
Date: Jul. 01, 2010
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