Assuntos
Doenças Autoimunes/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Infecções por Vírus Epstein-Barr/genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Linfoma/genética , Adolescente , Doenças Autoimunes/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Criança , Proteínas de Ligação a DNA/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Lactente , Linfoma/imunologia , Masculino , Linhagem , Mutação PuntualRESUMO
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.