title: The protein stannin binds 14-3-3zeta and modulates mitogen-activated protein kinase signaling.
abstract: The molecular mechanisms underlying the selective toxicity of trimethyltin (TMT) remain unclear. Stannin (Snn), a protein preferentially expressed in TMT-sensitive cells, provides a direct link to the molecular basis for TMT toxicity. Recent evidence demonstrated that Snn peptides bind and de-alkylate TMT to dimethyltin (DMT); Snn may mediate both TMT and DMT toxicity. In this study, we demonstrate that Snn co-immunoprecipitates with a scaffolding protein 14-3-3, specifically with 14-3-3zeta isotype. Consistent with this, a detailed amino acid sequence analysis shows that Snn contains a putative 14-3-3 protein-binding site located within its hydrophilic loop. In addition, we present the evidence that Snn overexpression results in reduced extracellular regulated kinase activation and increased p38 activation. In contrast, the activity of c-Jun N-terminal kinase did not change following Snn overexpression. This is the first evidence that demonstrates a direct interaction between Snn and MAPK signaling molecules. Together, these findings indicate a role of Snn in modulation of MAPK signaling pathways through its interactions with 14-3-3zeta.
authors.affiliation: Department of Pharmacology, Pennsylvania State University, Milton S. Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Collin E
authors.initials: CE
authors.lastname: Davidson
authors.forename: Brian E
authors.initials: BE
authors.lastname: Reese
authors.forename: Melvin L
authors.initials: ML
authors.lastname: Billingsley
authors.forename: Jong K
authors.initials: JK
authors.lastname: Yun
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology*; D051381:Rats; D014298:Trimethyltin Compounds / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D009479:Neuropeptides; D009498:Neurotoxins; D014298:Trimethyltin Compounds; C046488:trimethyltin; C075692:stannin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases