Gene Symbol: Ywhae
Description: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide
Alias: AU019196, 14-3-3 protein epsilon, 14-3-3 epsilon, 14-3-3E, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activatioprotein, epsilon polypeptide
Species: mouse
Products:     Ywhae

Top Publications

  1. Jin D, Lyu M, Kozak C, Jeang K. Function of 14-3-3 proteins. Nature. 1996;382:308 pubmed
  2. Liang X, Butterworth M, Peters K, Walker W, Frizzell R. An obligatory heterodimer of 14-3-3beta and 14-3-3epsilon is required for aldosterone regulation of the epithelial sodium channel. J Biol Chem. 2008;283:27418-25 pubmed publisher
  3. Liang X, Peters K, Butterworth M, Frizzell R. 14-3-3 isoforms are induced by aldosterone and participate in its regulation of epithelial sodium channels. J Biol Chem. 2006;281:16323-32 pubmed
    ..Our studies show that aldosterone increases the expression of 14-3-3beta, which interacts with phospho-Nedd4-2 to block its interaction with ENaC, thus enhancing sodium absorption by increasing apical membrane ENaC density. ..
  4. Ikeda M, Hikita T, Taya S, Uraguchi Asaki J, Toyo oka K, Wynshaw Boris A, et al. Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum Mol Genet. 2008;17:3212-22 pubmed publisher
    ..we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of ..
  5. Toyo oka K, Shionoya A, Gambello M, Cardoso C, Leventer R, Ward H, et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet. 2003;34:274-85 pubmed
    ..Here, we show that the gene encoding 14-3-3epsilon (YWHAE), one of a family of ubiquitous phosphoserine/threonine-binding proteins, is always deleted in individuals with ..
  6. Gittenberger de Groot A, Hoppenbrouwers T, Miquerol L, Kosaka Y, Poelmann R, Wisse L, et al. 14-3-3epsilon controls multiple developmental processes in the mouse heart. Dev Dyn. 2016;245:1107-1123 pubmed publisher
    ..These data suggest that 14-3-3?, in addition to left ventricular non-compaction (LVNC), might be linked to different forms of congenital heart disease (CHD). Developmental Dynamics 245:1107-1123, 2016. © 2016 Wiley Periodicals, Inc. ..
  7. Urschel S, Bassermann F, Bai R, Münch S, Peschel C, Duyster J. Phosphorylation of grb10 regulates its interaction with 14-3-3. J Biol Chem. 2005;280:16987-93 pubmed
    ..Based on these findings, we propose a regulatory circuitry involving a phosphorylation-regulated complex formation of Grb10 with 14-3-3 and Akt. ..
  8. Ziegler P, Teller S, Ha N, Giese B, Fraunholz M, Walther R. Phosphoproteomic identification of a PDX-1/14-3-3? interaction in pancreatic beta cells. Horm Metab Res. 2011;43:165-70 pubmed publisher
    ..We propose that 14-3-3? interacts directly with PDX-1 to regulate its cellular distribution in pancreatic beta cells. ..
  9. Cornell B, Toyo oka K. Deficiency of 14-3-3? and 14-3-3? by the Wnt1 promoter-driven Cre recombinase results in pigmentation defects. BMC Res Notes. 2016;9:180 pubmed publisher
    ..Our data obtained from the 14-3-3?/14-3-3?/Wnt1-Cre mice strongly indicate the importance of 14-3-3 proteins in the development of melanocyte lineages. ..

More Information


  1. Nefla M, Sudre L, Denat G, Priam S, Andre Leroux G, Berenbaum F, et al. The pro-inflammatory cytokine 14-3-3ε is a ligand of CD13 in cartilage. J Cell Sci. 2015;128:3250-62 pubmed publisher
    ..The 14-3-3ε-CD13 interaction could be a new therapeutic target in osteoarthritis. ..
  2. Winter S, Simboeck E, Fischle W, Zupkovitz G, Dohnal I, Mechtler K, et al. 14-3-3 proteins recognize a histone code at histone H3 and are required for transcriptional activation. EMBO J. 2008;27:88-99 pubmed
    ..Finally, siRNA-mediated loss of 14-3-3 proteins abolishes the transcriptional activation of HDAC1. Together our data indicate that 14-3-3 proteins are crucial mediators of histone phosphoacetylation signals. ..
  3. Li X, Song S, Liu Y, Ko S, Kao H. Phosphorylation of the histone deacetylase 7 modulates its stability and association with 14-3-3 proteins. J Biol Chem. 2004;279:34201-8 pubmed
    ..Together, our results suggest that calcium/calmodulin-dependent kinase I-mediated phosphorylation of HDAC7 acts, in part, to promote association of HDAC7 with 14-3-3 and stabilizes HDAC7. ..
  4. Gao C, Li X, Lam M, Liu Y, Chakraborty S, Kao H. CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14-3-3s. FEBS Lett. 2006;580:5096-104 pubmed
    ..Taken together, these results strongly suggest that CRM1 mediated-nuclear export of HDAC7 is independent of HDAC7 phosphorylation and its association with 14-3-3s. ..
  5. Liang X, Butterworth M, Peters K, Frizzell R. AS160 modulates aldosterone-stimulated epithelial sodium channel forward trafficking. Mol Biol Cell. 2010;21:2024-33 pubmed publisher
  6. Milton A, Khaire N, Ingram L, O Donnell A, La Thangue N. 14-3-3 proteins integrate E2F activity with the DNA damage response. EMBO J. 2006;25:1046-57 pubmed
    ..These results identify a new level of control on E2F activity and, at a more general level, suggest that 14-3-3 proteins integrate E2F activity with the DNA damage response. ..
  7. Clark K, Oelke A, Johnson M, Eilert K, Simpson P, Todd S. CD81 associates with 14-3-3 in a redox-regulated palmitoylation-dependent manner. J Biol Chem. 2004;279:19401-6 pubmed
    ..These finding suggest that CD81 signaling events could be mediated by 14-3-3 adapter proteins, and these signals may be dependent on cellular redox. ..
  8. Yingling J, Toyo oka K, Wynshaw Boris A. Miller-Dieker syndrome: analysis of a human contiguous gene syndrome in the mouse. Am J Hum Genet. 2003;73:475-88 pubmed
  9. Shen Y, Li N, Wu S, Zhou Y, Shan Y, Zhang Q, et al. Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells. Dev Cell. 2008;14:342-53 pubmed publisher
    ..Nudel facilitates cell migration by sequestering Cdc42GAP at the leading edge to stabilize active Cdc42 in response to extracellular stimuli. Excess active Cdc42 may in turn control its own activity by recruiting Cdc42GAP from Nudel. ..
  10. Cui C, Ren X, Liu D, Deng X, Qin X, Zhao X, et al. 14-3-3 epsilon prevents G2/M transition of fertilized mouse eggs by binding with CDC25B. BMC Dev Biol. 2014;14:33 pubmed publisher
    ..Our previous studies demonstrated that 14-3-3? (YWHAE) is responsible for maintaining prophase | arrest in mouse oocyte...
  11. Kim H, Han J, Park J, Oh M, James S, Chang S, et al. Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation. J Biol Chem. 2008;283:977-87 pubmed
    ..These results highlight signaling events in the regulation of delta-catenin-induced dendrogenesis and spine morphogenesis. ..
  12. Sorokina E, Feinstein S, Zhou S, Fisher A. Intracellular targeting of peroxiredoxin 6 to lysosomal organelles requires MAPK activity and binding to 14-3-3?. Am J Physiol Cell Physiol. 2011;300:C1430-41 pubmed publisher
    ..These findings suggest that ERK and p38 MAPK regulate subcellular localization of Prdx6 by activation of 14-3-3? as a chaperone protein, resulting in its translocation to acidic organelles. ..
  13. Di Francesco L, Correani V, Fabrizi C, Fumagalli L, Mazzanti M, Maras B, et al. 14-3-3? marks the amyloid-stimulated microglia long-term activation. Proteomics. 2012;12:124-34 pubmed publisher
  14. Pramparo T, Libiger O, Jain S, Li H, Youn Y, Hirotsune S, et al. Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects. PLoS Genet. 2011;7:e1001331 pubmed publisher
    ..Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3?), and Ndel1 lead to neuronal migration defects in mouse and provide models of human ..
  15. Niu J, Scheschonka A, Druey K, Davis A, Reed E, Kolenko V, et al. RGS3 interacts with 14-3-3 via the N-terminal region distinct from the RGS (regulator of G-protein signalling) domain. Biochem J. 2002;365:677-84 pubmed
    ..This study describes a new level in the regulation of G-protein signalling, in which the inhibitors of G-proteins, RGS proteins, can themselves be regulated by phosphorylation and binding 14-3-3. ..
  16. Hippenmeyer S, Youn Y, Moon H, Miyamichi K, Zong H, Wynshaw Boris A, et al. Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration. Neuron. 2010;68:695-709 pubmed publisher
    ..Comparisons with previous genetic perturbations of Lis1 and Ndel1 also suggest a surprising degree of cell-nonautonomous function for these proteins in regulating neuronal migration. ..
  17. Chong S, Tanigami A, Roschke A, Ledbetter D. 14-3-3 epsilon has no homology to LIS1 and lies telomeric to it on chromosome 17p13.3 outside the Miller-Dieker syndrome chromosome region. Genome Res. 1996;6:735-41 pubmed
    ..3). However, 14-3-3 epsilon lies telomeric to LIS1 and outside the Miller-Dieker syndrome chromosome region but in a region frequently deleted in several types of cancer, and is a reasonable candidate tumor suppressor gene. ..
  18. Sadik G, Tanaka T, Kato K, Yamamori H, Nessa B, Morihara T, et al. Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation. J Neurochem. 2009;108:33-43 pubmed publisher
    ..Also as the phosphorylation at Ser214 is up-regulated in Alzheimer's disease brain, tau's interaction with 14-3-3 might be involved in the pathology of this disease. ..
  19. Machka C, Kersten M, Zobawa M, Harder A, Horsch M, Halder T, et al. Identification of Dll1 (Delta1) target genes during mouse embryogenesis using differential expression profiling. Gene Expr Patterns. 2005;6:94-101 pubmed
    ..The large set of regulated genes identified in this differential expression profiling approach is an important resource for further functional studies. ..
  20. Kosaka Y, Cieslik K, Li L, Lezin G, Maguire C, Saijoh Y, et al. 14-3-3? plays a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle. Mol Cell Biol. 2012;32:5089-102 pubmed publisher
    ..These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3? as a new candidate gene in congenital human cardiomyopathies. ..
  21. Eilers A, Sundwall E, Lin M, Sullivan A, Ayer D. A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex. Mol Cell Biol. 2002;22:8514-26 pubmed
    ..Second, an extracellular signal(s) must overcome the cytoplasmic localization function imparted by CRM1 and 14-3-3 binding to the N terminus of MondoA. ..
  22. Jafar Nejad P, Ward C, Richman R, Orr H, Zoghbi H. Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. Proc Natl Acad Sci U S A. 2011;108:2142-7 pubmed publisher
    ..These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis...
  23. Baxter H, Liu W, Forster J, Aitken A, Fraser J. Immunolocalisation of 14-3-3 isoforms in normal and scrapie-infected murine brain. Neuroscience. 2002;109:5-14 pubmed
    ..The fact that isoform labelling in terminal scrapie CNS is lost in some brain areas, but increases in others, suggests that the processing of these proteins during neurodegeneration may be much more complex than previously recognised. ..
  24. Kao H, Verdel A, Tsai C, Simon C, Juguilon H, Khochbin S. Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J Biol Chem. 2001;276:47496-507 pubmed
    ..The data also show that the cellular concentration of factors such as 14-3-3, CaMK I, and other yet unknown molecules may determine the subcellular localization of an individual HDAC member in a cell type and HDAC-specific manner. ..
  25. Finlin B, Andres D. Phosphorylation-dependent association of the Ras-related GTP-binding protein Rem with 14-3-3 proteins. Arch Biochem Biophys. 1999;368:401-12 pubmed
    ..These results suggest that 14-3-3 may allow the recruitment of distinct proteins that participate in Rem-mediated signal transduction pathways. ..
  26. Wachi T, Cornell B, Toyo oka K. Complete ablation of the 14-3-3epsilon protein results in multiple defects in neuropsychiatric behaviors. Behav Brain Res. 2017;319:31-36 pubmed publisher
    Previous studies show that mice with Ywhae deficiency show abnormalities in brain development including defects in neuronal migration of post-mitotic pyramidal neurons as well as neuronal differentiation and proliferation in neuronal ..
  27. McConnell J, Armstrong J, Hodges P, Bard J. The mouse 14-3-3 epsilon isoform, a kinase regulator whose expression pattern is modulated in mesenchyme and neuronal differentiation. Dev Biol. 1995;169:218-28 pubmed
    ..The results as a whole thus argue for the 14-3-3 epsilon isoform playing roles in neural development and in early mesenchyme, with this latter function being lost or replaced as the tissue differentiates. ..
  28. Kim H, Lee J, Lee Y. Regulation of poly(A) polymerase by 14-3-3epsilon. EMBO J. 2003;22:5208-19 pubmed
    ..These data suggest that 14-3-3epsilon is involved in regulating both the activity and the nuclear/ cytoplasmic partitioning of PAP through the phosphorylation-dependent interaction. ..
  29. Barbash O, Lee E, Diehl J. Phosphorylation-dependent regulation of SCF(Fbx4) dimerization and activity involves a novel component, 14-3-3?. Oncogene. 2011;30:1995-2002 pubmed publisher
    ..Collectively, the current results suggest a model wherein 14-3-3? binds to Ser12-phosphorylated Fbx4 to mediate dimerization and function. ..
  30. Angrand P, Segura I, Volkel P, Ghidelli S, Terry R, Brajenovic M, et al. Transgenic mouse proteomics identifies new 14-3-3-associated proteins involved in cytoskeletal rearrangements and cell signaling. Mol Cell Proteomics. 2006;5:2211-27 pubmed
  31. Hamilton B, Smith D, Mueller K, Kerrebrock A, Bronson R, van Berkel V, et al. The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression. Neuron. 1997;18:711-22 pubmed
    ..The vibrator phenotype is suppressed in one intercross. We performed a complete genome scan and mapped a major suppressor locus (Mvb-1) to proximal chromosome 19. ..
  32. Toyo oka K, Wachi T, Hunt R, Baraban S, Taya S, Ramshaw H, et al. 14-3-3ε and ζ regulate neurogenesis and differentiation of neuronal progenitor cells in the developing brain. J Neurosci. 2014;34:12168-81 pubmed publisher
    ..Our findings provide new evidence that 14-3-3 proteins play important roles in neurogenesis and neuronal migration via the regulation of distinct signaling cascades. ..
  33. Meng J, Cui C, Liu Y, Jin M, Wu D, Liu C, et al. The role of 14-3-3? interaction with phosphorylated Cdc25B at its Ser321 in the release of the mouse oocyte from prophase I arrest. PLoS ONE. 2013;8:e53633 pubmed publisher
    ..Taken together, these data indicate that Ser321 of Cdc25B is the specific binding site for 14-3-3? binding, and that 14-3-3? is the significant factor in Cdc25B regulation during meiotic resumption of GV stage. ..
  34. Castelli M, Camps M, Gillieron C, Leroy D, Arkinstall S, Rommel C, et al. MAP kinase phosphatase 3 (MKP3) interacts with and is phosphorylated by protein kinase CK2alpha. J Biol Chem. 2004;279:44731-9 pubmed
    ..In addition, we demonstrated that CK2 selectively phosphorylates MKP3, suggesting cross-regulation between CK2alpha and MKP3, as well as a modulation of ERK2-MAPK signaling by CK2alpha via MKP3. ..
  35. Yacoubian T, Slone S, Harrington A, Hamamichi S, Schieltz J, Caldwell K, et al. Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease. Cell Death Dis. 2010;1:e2 pubmed publisher
  36. Wang W, Shakes D. Molecular evolution of the 14-3-3 protein family. J Mol Evol. 1996;43:384-98 pubmed
    ..A possible ancestral 14-3-3 sequence is proposed. ..
  37. Li X, Wang Q, Pan N, Lee S, Zhao Y, Chait B, et al. Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease. PLoS ONE. 2011;6:e17153 pubmed publisher
    ..Furthermore, the reduction of phosphorylation/14-3-3 binding of LRRK2 due to the common familial PD-related mutations provides novel insight into the pathogenic mechanism of LRRK2-linked PD. ..
  38. Mizuno E, Kitamura N, Komada M. 14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase. Exp Cell Res. 2007;313:3624-34 pubmed
    ..We conclude that UBPY is catalytically inhibited in a phosphorylation-dependent manner by 14-3-3s during the interphase, and this regulation is cancelled in the M phase. ..
  39. Lonic A, Barry E, Quach C, Kobe B, Saunders N, Guthridge M. Fibroblast growth factor receptor 2 phosphorylation on serine 779 couples to 14-3-3 and regulates cell survival and proliferation. Mol Cell Biol. 2008;28:3372-85 pubmed publisher
    ..In this regard, we have identified conserved putative phosphotyrosine/phosphoserine motifs in the cytoplasmic domains of diverse cell surface receptors, suggesting that they may perform important functional roles beyond the FGFRs. ..
  40. Wang X, Grammatikakis N, Siganou A, Stevenson M, Calderwood S. Interactions between extracellular signal-regulated protein kinase 1, 14-3-3epsilon, and heat shock factor 1 during stress. J Biol Chem. 2004;279:49460-9 pubmed
    ..Association of HSF1 with ERK and 14-3-3epsilon during heat shock may thus modulate the amplitude of the response and lead to efficient termination of HSP expression on resumption of growth conditions. ..
  41. Hirotsune S, Pack S, Chong S, Robbins C, Pavan W, Ledbetter D, et al. Genomic organization of the murine Miller-Dieker/lissencephaly region: conservation of linkage with the human region. Genome Res. 1997;7:625-34 pubmed
    ..Our results demonstrate that the MDS region is conserved between human and mouse. This conservation of linkage suggests that the mouse can be used to model microdeletions that occur in ILS and MDS. ..
  42. Ramsey A, Milenkovic M, Oliveira A, Escobedo Lozoya Y, Seshadri S, Salahpour A, et al. Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner. Proc Natl Acad Sci U S A. 2011;108:5795-800 pubmed publisher
    ..The synaptic reduction of DISC1 and 14-3-3? is developmentally correlated with the age-dependent decrease in striatal spine density. ..
  43. Han L, Wong D, Dhaka A, Afar D, White M, Xie W, et al. Protein binding and signaling properties of RIN1 suggest a unique effector function. Proc Natl Acad Sci U S A. 1997;94:4954-9 pubmed
    ..These data suggest that RIN1 is able to mediate multiple signals. A differential pattern of expression and alternate splicing indicate several levels of RIN1 regulation. ..
  44. Cornell B, Wachi T, Zhukarev V, Toyo oka K. Regulation of neuronal morphogenesis by 14-3-3epsilon (Ywhae) via the microtubule binding protein, doublecortin. Hum Mol Genet. 2016;25:4405-4418 pubmed publisher
    ..Our findings provide the first evidence of cellular pathology in 17p13.3 microduplication syndrome. ..
  45. Sekiguchi H, Iritani S, Habuchi C, Torii Y, Kuroda K, Kaibuchi K, et al. Impairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia. Brain Res. 2011;1392:47-53 pubmed publisher
    ..There is thought to be a dysfunction of a neurotransmitter such as dopamine and noradrenalin in the prefrontal cortex of these knockout mice. ..
  46. Yam P, Kent C, Morin S, Farmer W, Alchini R, Lepelletier L, et al. 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing. Neuron. 2012;76:735-49 pubmed publisher
    ..Therefore, we identify a 14-3-3 protein-dependent mechanism for a cell-intrinsic temporal switch in the polarity of axon turning responses. ..
  47. Stead R, Proud C. Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a). FEBS Lett. 2013;587:2623-8 pubmed publisher
    ..Our findings have potentially important implications for the use of rapamycin and its analogues in cancer therapy, suggesting that inhibitors of mTOR and Mnk (or Mnk2) may be more efficacious than rapalogs alone. ..
  48. Kislinger T, Cox B, Kannan A, Chung C, Hu P, Ignatchenko A, et al. Global survey of organ and organelle protein expression in mouse: combined proteomic and transcriptomic profiling. Cell. 2006;125:173-86 pubmed
    ..This molecular compendium, fully accessible via a searchable web-browser interface, serves as a reliable reference of the expressed tissue and organelle proteomes of a leading model mammal. ..
  49. Yee K, Yagi H, Matsuoka R, Nakanishi T, Furukawa T. Transrepression activity of T-box1 in a gene regulation network in mouse cells. Gene. 2012;510:162-70 pubmed publisher
    ..We identified 127 genes that were potentially transrepressed by Tbx1. Of the transrepressed genes, we focused on Ywhae and C1qbp and carried out promoter assays...
  50. Neukamm S, Ott J, Dammeier S, Lehmann R, Haring H, Schleicher E, et al. Phosphorylation of serine 1137/1138 of mouse insulin receptor substrate (IRS) 2 regulates cAMP-dependent binding to 14-3-3 proteins and IRS2 protein degradation. J Biol Chem. 2013;288:16403-15 pubmed publisher
    ..We present serine 1137/1138 as novel cAMP-dependent phosphorylation sites on IRS2 and show their importance in 14-3-3 binding and IRS2 protein stability. ..