title: Negative regulation of the RalGAP complex by 14-3-3.
abstract: RGC1 and RGC2 comprise a functional RalGAP complex (RGC) that suppresses RalA activity. The PI3-kinase/Akt signaling pathway activates RalA through phosphorylation-mediated inhibition of the RGC. Here we identify a novel phosphorylation-dependent interaction between 14-3-3 and the RGC. 14-3-3 binds to the complex through an Akt-phosphorylated residue, threonine 715, on RGC2. Interaction with 14-3-3 does not alter in vitro activity of the GTPase-activating protein complex. However, blocking the interaction between 14-3-3 and RGC2 in cells increases suppression of RalA activity by the RGC, suggesting that 14-3-3 inhibits the complex through a non-catalytic mechanism. Together, these data show that 14-3-3 negatively regulates the RGC downstream of the PI3-kinase/Akt signaling pathway.
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Dara
authors: D
authors: Leto
authors: Maeran
authors: M
authors: Uhm
authors: Anja
authors: A
authors: Williams
authors: Xiao-wei
authors: XW
authors: Chen
authors: Alan R
authors: AR
authors: Saltiel
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D020816:Amino Acid Motifs; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D000077191:Wortmannin; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D000730:Androstadienes; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; C495326:RALGAPA1 protein, human; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D019204:GTP-Binding Proteins; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins; D000077191:Wortmannin
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