title: Direct interaction between scaffolding proteins RACK1 and 14-3-3ζ regulates brain-derived neurotrophic factor (BDNF) transcription.
abstract: RACK1 is a scaffolding protein that spatially and temporally regulates numerous signaling cascades. We previously found that activation of the cAMP signaling pathway induces the translocation of RACK1 to the nucleus. We further showed that nuclear RACK1 is required to promote the transcription of the brain-derived neurotrophic factor (BDNF). Here, we set out to elucidate the mechanism underlying cAMP-dependent RACK1 nuclear translocation and BDNF transcription. We identified the scaffolding protein 14-3-3ζ as a direct binding partner of RACK1. Moreover, we found that 14-3-3ζ was necessary for the cAMP-dependent translocation of RACK1 to the nucleus. We further observed that the disruption of RACK1/14-3-3ζ interaction with a peptide derived from the RACK1/14-3-3ζ binding site or shRNA-mediated 14-3-3ζ knockdown inhibited cAMP induction of BDNF transcription. Together, these data reveal that the function of nuclear RACK1 is mediated through its interaction with 14-3-3ζ. As RACK1 and 14-3-3ζ are two multifunctional scaffolding proteins that coordinate a wide variety of signaling events, their interaction is likely to regulate other essential cellular functions.
authors: Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
authors: Jérémie
authors: J
authors: Neasta
authors: Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
authors: Patrick A
authors: PA
authors: Kiely
authors: Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608.
authors: Dao-Yao
authors: DY
authors: He
authors: Department of Chemistry, Heriot-Watt University, Riccarton Campus, Edinburgh EH14AS, Scotland, United Kingdom.
authors: David R
authors: DR
authors: Adams
authors: Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
authors: Rosemary
authors: R
authors: O'Connor
authors: Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608. Electronic address: dron@gallo.ucsf.edu.
authors: Dorit
authors: D
authors: Ron
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D048948:14-3-3 Proteins; D019208:Brain-Derived Neurotrophic Factor; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins