Skip to main content
SpringerLink
Log in

Arachidonic Acid Binds 14-3-3ζ, Releases 14-3-3ζ from Phosphorylated BAD and Induces Aggregation of 14-3-3ζ

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Polyunsaturated fatty acids, like arachidonic acid, can bind proteins and affect their function. The 14-3-3 proteins bind phosphorylated sites on a diverse array of client proteins and, in this way, are involved in many intracellular signaling pathways. In this study, we used a novel approach to discover that 14-3-3ζ is able to directly bind arachidonic acid. Furthermore, arachidonic acid, at physiological concentrations, reduced the binding of 14-3-3ζ to phosphorylated BAD, an interaction that is important in regulating apoptosis. In addition, high concentrations of arachidonic acid caused the polymerization of 14-3-3ζ, an event observed in neurodegenerative disorders. Taken together, these results indicate that arachidonic acid directly interacts with 14-3-3ζ and that this interaction may be important in both normal and pathological cellular events. If so, then factors that mediate the release, metabolism and reacylation of arachidonic acid into membranes represent key points of regulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AA:

Arachidonic acid

DHA:

Docosahexaenoic acid

LDH-A:

l-Lactate dehydrogenase A chain

MALDI-TOF:

Matrix assisted laser desorption/ionization-time of flight

pBAD:

Phosphorylated BAD

PUFA:

Polyunsaturated fatty acid

RBL:

Rat basophilic leukemia

References

  1. Tzivion G, Avruch J (2002) 14-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation. J Biol Chem 277:3061–3064

    Article  PubMed  CAS  Google Scholar 

  2. Bridges D, Moorhead GB (2005) 14-3-3 proteins: a number of functions for a numbered protein. Sci STKE re10/DC2

  3. Darling DL, Yingling J, Wynshaw-Boris A (2005) Role of 14-3-3 proteins in eukaryotic signaling and development. Curr Top Dev Biol 68:281–315

    Article  PubMed  CAS  Google Scholar 

  4. Dougherty MK, Morrison DK (2004) Unlocking the code of 14-3-3. J Cell Sci 117:1875–1884

    Article  PubMed  CAS  Google Scholar 

  5. Masters SC, Fu H (2001) 14-3-3 proteins mediate an essential anti-apoptotic signal. J Biol Chem 276:45193–45200

    Article  PubMed  CAS  Google Scholar 

  6. Porter GW, Khuri FR, Fu H (2006) Dynamic 14-3-3/client protein interactions integrate survival and apoptotic pathways. Semin Cancer Biol 16:193–202

    Article  PubMed  CAS  Google Scholar 

  7. Yang H, Masters SC, Wang H, Fu H (2001) The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta. Biochim Biophys Acta 1547:313–319

    PubMed  CAS  Google Scholar 

  8. Subramanian R, Masters S, Zhang H, Fu H (2001) Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis. Exp Cell Res 271:142–151

    Article  PubMed  CAS  Google Scholar 

  9. Chiang CW, Kanies C, Kim KW et al (2003) Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. Mol Cell Biol 23:6350–6362

    Article  PubMed  CAS  Google Scholar 

  10. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628

    Article  PubMed  CAS  Google Scholar 

  11. Maslyar DJ, Aoki M, Vogt PK (2001) The growth-promoting activity of the Bad protein in chicken embryo fibroblasts requires binding to protein 14-3-3. Oncogene 20:5087–5092

    Article  PubMed  CAS  Google Scholar 

  12. Berg D, Holzmann C, Riess O (2003) 14-3-3 proteins in the nervous system. Nat Rev Neurosci 4:752–762

    Article  PubMed  CAS  Google Scholar 

  13. Layfield R, Fergusson J, Aitken A, Lowe J, Landon M, Mayer RJ (1996) Neurofibrillary tangles of Alzheimer’s disease brains contain 14-3-3 proteins. Neurosci Lett 209:57–60

    Article  PubMed  CAS  Google Scholar 

  14. Fountoulakis M, Cairns N, Lubec G (1999) Increased levels of 14-3-3 gamma and epsilon proteins in brain of patients with Alzheimer’s disease and Down syndrome. J Neural Transm Suppl 57:323–335

    PubMed  CAS  Google Scholar 

  15. Umahara T, Uchihara T, Tsuchiya K et al (2004) 14-3-3 proteins and zeta isoform containing neurofibrillary tangles in patients with Alzheimer’s disease. Acta Neuropathol (Berl) 108:279–286

    Article  CAS  Google Scholar 

  16. Soulié C, Nicole A, Delacourte A, Ceballos-Picot I (2004) Examination of stress-related genes in human temporal versus occipital cortex in the course of neurodegeneration: involvement of 14-3-3ζ in this dynamic process. Neurosci Lett 365:1–5

    Article  PubMed  CAS  Google Scholar 

  17. Waelter S, Boeddrich A, Lurz R et al (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407

    PubMed  CAS  Google Scholar 

  18. Umahara T, Uchihara T, Tsuchiya K et al (2001) Immunolocalization of 14-3-3 isoforms in brains with Pick body disease. Neurosci Lett 371:215–219

    Article  CAS  Google Scholar 

  19. Wiltfang J, Otto M, Baxter HC et al (1999) Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurochem 73:2485–2490

    Article  PubMed  CAS  Google Scholar 

  20. Krasnianski A, Meissner B, Schulz-Schaeffer W et al (2006) Clinical features and diagnosis of the MM2 cortical subtype of sporadic Creutzfeldt-Jakob disease. Arch Neurol 63:876–880

    Article  PubMed  Google Scholar 

  21. Hayakawa M, Ishida N, Takeuchi K et al (1993) Arachidonic acid-selective cytosolic phospholipase A2 is crucial in the cytotoxic action of tumor necrosis factor. J Biol Chem 268:11290–11295

    PubMed  CAS  Google Scholar 

  22. Levrat C, Louisot P (1996) Increase of mitochondrial PLA2-released fatty acids is an early event in tumor necrosis factor alpha-treated WEHI-164 cells. Biochem Biophys Res Commun 221:531–538

    Article  PubMed  CAS  Google Scholar 

  23. Baskin DS, Ngo H, Didenko V (2003) Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci 74:361–368

    Article  PubMed  CAS  Google Scholar 

  24. Woo KJ, Lee TJ, Bae JH et al (2006) Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells. Mol Carcinogen 45:657–666

    Article  CAS  Google Scholar 

  25. Pérez R, Matabosch X, Llebaria A, Balboa MA, Balsinde J (2006) Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells. J Lipid Res 47:484–491

    Article  PubMed  CAS  Google Scholar 

  26. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    PubMed  CAS  Google Scholar 

  27. Wilson DM, Binder LI (1997) Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am J Pathol 150:2181–2195

    PubMed  CAS  Google Scholar 

  28. King ME, Gamblin TC, Kuret J, Binder LI (2000) Differential assembly of human tau isoforms in the presence of arachidonic acid. J Neurochem 74:1749–1757

    Article  PubMed  CAS  Google Scholar 

  29. Luo ZJ, Zhang XF, Rapp U, Avruch J (1995) Identification of the 14.3.3 zeta domains important for self-association and Raf binding. J Biol Chem 270:23681–23687

    Article  PubMed  CAS  Google Scholar 

  30. Brock TG, Paine RI, Peters-Golden M (1994) Localization of 5-lipoxygenase to the nucleus of unstimulated rat basophilic leukemia cells. J Biol Chem 269:22059–22066

    PubMed  CAS  Google Scholar 

  31. Raza H, Pongubala J, Sorof S (1989) Specific high affinity binding of lipoxygenase metabolites of arachidonic acid by liver fatty acid binding protein. Biochem Biophys Res Commun 161:448–455

    Article  PubMed  CAS  Google Scholar 

  32. Roth D, Morgan A, Martin H et al (1994) Characterization of 14-3-3 proteins in adrenal chromaffin cells and demonstration of isoform-specific phospholipid binding. Biochem J 301:305–310

    PubMed  CAS  Google Scholar 

  33. Jones DH, Martin H, Madrazo J et al (1995) Expression and structural analysis of 14-3-3 proteins. J Mol Biol 245:375–384

    Article  PubMed  CAS  Google Scholar 

  34. Lawrence JW, Kroll DJ, Eacho PI (2000) Ligand-dependent interaction of hepatic fatty acid-binding protein with the nucleus. J Lipid Res 41:1390–1401

    PubMed  CAS  Google Scholar 

  35. Huang H, Starodub O, McIntosh A, Kier AB, Schroeder F (2002) Liver fatty acid-binding protein targets fatty acids to the nucleus. Real time confocal and multiphoton fluorescence imaging in living cells. J Biol Chem 277:29139–23151

    Article  PubMed  CAS  Google Scholar 

  36. Phillis JW, O’Regan MH (2004) A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res Brain Res Rev 44:13–47

    Article  PubMed  CAS  Google Scholar 

  37. Baethmann A, Maier-Hauff K, Schürer L et al (1989) Release of glutamate and of free fatty acids in vasogenic brain edema. J Neurosurg 70:578–291

    Article  PubMed  CAS  Google Scholar 

  38. Siesjö BK, Ingvar M, Westerberg E (1982) The influence of bicuculline-induced seizures on free fatty acid concentrations in cerebral cortex, hippocampus, and cerebellum. J Neurochem 39:796–802

    Article  PubMed  Google Scholar 

  39. Yoshida S, Harik SI, Busto R, Santiso M, Martinez E, Ginsberg MD (1984) Free fatty acids and energy metabolites in ischemic cerebral cortex with noradrenaline depletion. J Neurochem 42:711–717

    Article  PubMed  CAS  Google Scholar 

  40. Meller R, Schindler CK, Chu XP et al (2003) Seizure-like activity leads to the release of BAD from 14-3-3 protein and cell death in hippocampal neurons in vitro. Cell Death Differ 10:539–547

    Article  PubMed  CAS  Google Scholar 

  41. Chen XQ, Fung YW, Yu AC (2005) Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes. J Cereb Blood Flow Metab 25:338–347

    Article  PubMed  CAS  Google Scholar 

  42. Perrin RJ, Woods WS, Clayton DF, George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958–41962

    Article  PubMed  CAS  Google Scholar 

  43. Hashiguchi M, Sobue K, Paudel H (2000) 14-3-3ζ is an effector of tau protein phosphorylation. J Biol Chem 275:25247–25254

    Article  PubMed  CAS  Google Scholar 

  44. Hernández F, Cuadros R, Avila J (2004) Zeta 14-3-3 protein favours the formation of human tau fibrillar polymers. Neurosci Lett 357:143–146

    Article  PubMed  CAS  Google Scholar 

  45. Sugimori K, Kobayashi K, Kitamura T, Sudo S, Koshino Y (2007) 14-3-3 protein beta isoform is associated with 3-repeat tau neurofibrillary tangles in Alzheimer’s disease. Psychiatry Clin Neurosci 61:159–167

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by generous funding from the Undergraduate Research Opportunities Program at the University of Michigan, as well as by National Institutes of Health Grant R01 AI43574. The technical expertise of John Allard is also acknowledged.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA

    Thomas G. Brock

Authors
  1. Thomas G. Brock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas G. Brock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brock, T.G. Arachidonic Acid Binds 14-3-3ζ, Releases 14-3-3ζ from Phosphorylated BAD and Induces Aggregation of 14-3-3ζ. Neurochem Res 33, 801–807 (2008). https://doi.org/10.1007/s11064-007-9498-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9498-3

Keywords

Search

Navigation