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VOOZH | about |
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VOOZH | about |
*601288
Table of Contents
Alternative titles; symbols
HGNC Approved Gene Symbol: YWHAZ
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38) : 8:100,916,523-100,953,382 (from NCBI)
The highly conserved 14-3-3 proteins are found in both plants and mammals. Some have been shown to be involved in the activation of c-Raf (164760) by their participation in the protein kinase C signaling pathway (see 176960). Leffers et al. (1993) reported the cloning of 14-3-3-zeta. See YWHAH (113508) and YWHAB (601289).
Watanabe et al. (1994) isolated the rat zeta isoform of 14-3-3 from rat brain. The deduced 245-amino acid protein shares high sequence homology with other 14-3-3 subtypes. The zeta mRNA was widely expressed in various gray matter brain regions, including the neocortex, hippocampus, caudate-putamen, thalamus, cerebellar cortex, and several brain stem nuclei. A human protein with phospholipase A2 activity was shown to be the zeta subtype of the 14-3-3 protein (Zupan et al., 1992).
By phylogenetic analysis, Anton-Galindo et al. (2022) confirmed the presence of a human YWHAZ ortholog in zebrafish. The zebrafish 14-3-3 protein was most closely related to the human YWHAZ protein. In situ hybridization showed that ywhaz expression was panneuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum.
Crystal Structure
The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997) identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of YWHAZ complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6-angstrom resolution. The authors showed that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD (603167), and Cbl.
Cryoelectron Microscopy
Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF (164757) in complexes with MEK1 (176872) and a 14-3-3 dimer of eta (YWHAH; 113508) and zeta (YWHAZ). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer.
The binding of insulin (176730) to its receptor induces the phosphorylation of the cytosolic substrates IRS1 (147545) and IRS2 (600797), which associate with several Src homology-2 (SH2) domain-containing proteins. To identify unique IRS1-binding proteins, Ogihara et al. (1997) screened a human heart cDNA expression library with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 protein family, 14-3-3-zeta and -epsilon (YWHAE; 605066). 14-3-3 protein has been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells, Chinese hamster ovary cells, and bovine brain tissue. The amount of 14-3-3 protein associated with IRS1 was not affected by insulin stimulation but was increased significantly by treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. The authors identified a putative 14-3-3 protein-binding site within the phosphotyrosine-binding (PTB) domain of IRS1. Ogihara et al. (1997) suggested that the association with 14-3-3 protein may play a role in the regulation of insulin sensitivity by interrupting the association between the insulin receptor and IRS1.
Using 2-hybrid experiments, Han et al. (1997) demonstrated interaction between murine Ywhaz and the RAS-binding domain of RIN1 (605965).
Using in vitro pull-down assays, Powell et al. (2002) showed that recombinant 14-3-3-zeta interacted directly with both recombinant and endogenous protein kinase B (PKB, or AKT1; 164730) within embryonic kidney cell lysates. They found that recombinant PKB phosphorylated 14-3-3-zeta in an in vitro kinase assay, and transfection of active PKB into embryonic kidney cells resulted in phosphorylation of 14-3-3-zeta. By mutation analysis, Powell et al. (2002) determined that the phosphate acceptor was serine-58. They also showed that phosphorylation did not result in 14-3-3-zeta dimerization.
Serotonin N-acetyltransferase (AANAT; 600950) controls daily changes in the production and circulating levels of melatonin. Zheng et al. (2003) studied the significance of the phosphorylation of AANAT using a semisynthetic enzyme in which a nonhydrolyzable phosphoserine/threonine mimetic, phosphonomethylenealanine (Pma), was incorporated at position 31 (AANAT-Pma31). The results of studies in which AANAT-Pma31 and related analogs were injected into cells provided the first evidence that threonine-31 phosphorylation controls AANAT stability in the context of the intact cells by binding to 14-3-3-zeta protein. Zheng et al. (2003) concluded that their findings established threonine-31 phosphorylation as an essential element in the intracellular regulation of melatonin production.
Using a yeast 2-hybrid screen, Birkenfeld et al. (2003) identified rat zetin-1 (BSPRY; 619683) as an interacting partner of the zeta isoform of 14-3-3 proteins. Immunoprecipitation and immunocytochemical analyses revealed that the 2 proteins interacted and colocalized in transfected COS-7 cells.
By coimmunoprecipitation and tandem mass spectrometric analysis, Tian et al. (2004) found that 14-3-3-zeta is a beta-catenin (116806)-interacting protein. 14-3-3-zeta enhanced beta-catenin-dependent transcription by stabilizing beta-catenin in the cytoplasm. Furthermore, 14-3-3-zeta facilitated activation of beta-catenin by AKT and colocalized with activated Akt in mouse intestinal stem cells. Tian et al. (2004) proposed that AKT phosphorylates beta-catenin, leading to 14-3-3-zeta binding and stabilization of beta catenin.
Li et al. (2010) found a significant association between amplification of a region on chromosome 8q22 and de novo chemoresistance to anthracyclines and metastatic recurrence in human breast cancer (114480). Within this region, overexpression of both the YWHAZ and LAPTM4B (613296) genes was found to correlate with the observations. Knockdown of either of these genes using siRNA resulting in sensitivity of tumor cells to anthracyclines. Extensive in vitro studies confirmed the effect. Further studies indicated that LAPTM4B resulted in sequestration of anthracycline and delayed entry into the nucleus, whereas YWHAZ likely protected cells from apoptosis. The findings were specific to anthracyclines. An Editorial Expression of Concern was published for the article of Li et al. (2010).
Using proteomics and mass spectrometric analysis, Leivonen et al. (2011) identified 14-3-3-zeta, SHMT2 (138450), and AKR1C2 (600450) as major targets of microRNA-193B (MIR193B; 614734) in MCF-7 human breast cancer cells. Cotransfection experiments confirmed that MIR193B downregulated expression of reporter genes containing the 3-prime UTRs of SHMT2 or YWHAZ or the 5-prime UTR of AKR1C2. Neutralization of MIR193B with anti-MIR193B led to elevated SHMT2 and AKR1C2 protein levels, with lesser upregulation of YWHAZ protein. Specific combinations of knockdowns of these target genes via small interfering RNAs inhibited growth in MCF-7 cells.
By coimmunoprecipitation analysis of HeLa cell lysates, Mizuno et al. (2007) showed that the 14-3-3 proteins YWHAE, YWHAG (605356), and YWHAZ bound mouse Usp8 (603158). Binding of 14-3-3 proteins to Usp8 was inhibited by phosphatase treatment, by mutating the consensus 14-3-3-binding motif in Usp8, or by competition with a phosphorylated 14-3-3-binding peptide. The authors identified ser680 within the 14-3-3-binding motif as the major phosphorylation site of mouse Usp8. Mutation of ser680 led to enhanced ubiquitin isopeptidase activity of Usp8 against polyubiquitin chains and human EGFR (131550). Addition of mouse Ywhae inhibited USP8 activity. Usp8 was dephosphorylated at ser680 and dissociated from 14-3-3 proteins in M phase, resulting in enhanced Usp8 activity during cell division. Mizuno et al. (2007) concluded that USP8 is catalytically inhibited in a phosphorylation-dependent manner by 14-3-3 proteins during interphase and that the regulation is discontinued in M phase.
Tommerup and Leffers (1996) mapped the YWHAZ gene to chromosome 2p25.2-p25.1 by fluorescence in situ hybridization. However, Hartz (2010) mapped the YWHAZ gene to chromosome 8q22.3 based on an alignment of the YWHAZ sequence (GenBank BC003623) with the genomic sequence (GRCh37).
In 5 unrelated patients with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified 5 different de novo heterozygous mutations in the YWHAZ gene (601288.0001-601288.0005), including 3 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. The first patient was identified through a genome sequencing research study, and the other 4 patients were subsequently identified through GeneMatcher or through data-sharing of exome sequencing. Detailed functional studies of 1 of the missense variants (S230W; 601288.0001) in Xenopus indicated that this mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway (see ANIMAL MODEL). Functional studies of the other YWHAZ variants and studies of patient cells were not performed. Of note, the patient (P1) with the S230W mutation also carried a heterozygous frameshift variant (c.4022_4023insGA) in the SCN8A gene (600702); heterozygous mutation in the SCN8A gene is associated with several neurologic disorders (see, e.g., CIAT, 614306). Patient 4 (see 601288.0004) also carried a de novo heterozygous frameshift variant (c.522_523insC) in the MAP3K14 gene (604655).
In a Chinese boy (proband) and his father (family WGS1059JH) with POPCHAS, Sun et al. (2022) identified a heterozygous missense mutation in the YWHAZ gene (E14K; 601288.0006). Functional studies of the variant were not performed. The proband was part of a cohort of 100 pediatric patients with global developmental delay/intellectual disability who underwent whole-genome sequencing. Hamosh (2025) noted that the E14K variant was not present in the gnomAD database (v4.1.0).
In 7 affected individuals spanning 3 generations of a family with POPCHAS, Wan et al. (2023) identified a heterozygous missense mutation in the YWHAZ gene (K49N; 601288.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including 1000 Genomes Project, Exome Sequencing Project, ExAC, and gnomAD. Studies of patient cells were not performed. Drosophila with CRISPR/Cas9-mediated knock-in of the K49N mutation showed significant memory defects on an olfactory test compared to controls, and some abnormal brain structures were observed in the mushroom body. No obvious seizure activity could be elicited with mechanical stimulus in mutant flies. RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila also caused memory defects and hyperactivity, but no seizure activity. There was no difference in cognitive function between ywhaz knockdown flies who were crossed with heterozygous K49N flies, suggesting that the K49N variant is not a gain-of-function variant, but rather results in a loss of function.
Popov et al. (2019) found that injection of the S230W mutation into Xenopus embryos caused dark pigmentation, possibly reflecting changes in cell shape, as well as defects in head structure and shortened and bent body axis compared to controls. The abnormalities induced by the mutant gene were more severe than those induced by overexpression of the wildtype gene. Further studies showed that the mutant Ywhaz protein was able to rescue defects induced by dominant-negative Fgfr1 (136350) and stimulated Raf-dependent Erk phosphorylation more efficiently than wildtype, consistent with a gain of function.
Wan et al. (2023) found that RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila caused memory defects and hyperactivity, but no seizure activity.
In a 9-year-old boy (patient 1) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.689C-G transversion (c.689C-G, NM_145690.2) in the YWHAZ gene, resulting in a ser230-to-trp (S230W) substitution in helix 6. The mutation, which was found by trio-based whole-genome sequencing, was not present in the gnomAD database. Detailed functional expression studies in Xenopus indicated that the S230W mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway compared to wildtype. Studies of patient cells were not performed. The patient also carried a heterozygous frameshift variant (c.4022_4023insGA) in the SCN8A gene (600702); heterozygous mutation in the SCN8A gene is associated with several neurologic disorders (see, e.g., CIAT, 614306).
In a 12-year-old girl (patient 2) with Popov-Change syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.157G-A transition (c.157G-A, NM_145690.2) in the YWHAZ gene, resulting in a gly53-to-arg (G53R) substitution in helix 3, which is involved in protein dimerization and ligand binding. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 17-year-old girl (patient 3) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.40G-T Popov et al. (2019) identified a de novo heterozygous c.434C-T transition (c.434C-T, NM_145690.2) in the YWHAZ gene, resulting in a ser145-to-leu (S145L) substitution in helix 6. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 9-year-old girl (patient 4) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.40G-T transversion (c.40G-T, NM_145690.2) in the YWHAZ gene, resulting in a glu14-to-ter (E14X) substitution. The variant was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient also carried a de novo heterozygous frameshift variant (c.522_523insC) in the MAP3K14 gene (604655).
In a 17-year-old boy (patient 5) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous 2-bp insertion (c.688_689insAT, NM_145690.2) in the YWHAZ gene, resulting in a frameshift and premature termination (Ser230TyrfsTer44). The mutation was found by trio-based exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
Anton-Galindo et al. (2022) found that ywhaz -/- zebrafish larvae displayed altered spontaneous neuronal activity and functional connectivity in the hindbrain. Adult ywhaz -/- fish displayed decreased levels of monoamines in the hindbrain and froze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. RT-PCR analysis revealed that loss of ywhaz function altered the expression of genes involved in the dopaminergic and serotonergic pathways.
In a Chinese boy (proband) and his father (family WGS1059GH) with Popov-Chang syndrome (POPCHAS; 618428), Sun et al. (2022) identified a heterozygous c.40G-A transition in the YWHAZ gene, resulting in a glu14-to-lys (E14K) substitution. The mutation appeared to occur de novo in the father, since it was not found in his unaffected parents. Functional studies of the variant were not performed. The boy (proband) was part of a cohort of 110 pediatric Chinese patients with global developmental delay who underwent whole-genome sequencing. Hamosh (2025) noted that the E14K variant was not present in the gnomAD database (v4.1.0).
In 7 affected individuals spanning 3 generations of a family with Popov-Chang syndrome (POPCHAS; 618428), Wan et al. (2023) identified a heterozygous c.147A-T transversion (c.147A-T, NM_001135699.1) in the YWHAZ gene, resulting in a lys49-to-asn (K49N) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including 1000 Genomes Project, Exome Sequencing Project, ExAC, and gnomAD. The authors stated in the text that 4 affected family members with hyperactivity/irritability also carried variants in 4 other genes (ARHGAP4, AGPS, APOL3, and KREMEN1), suggesting that these genes may be associated with hyperactivity or interact with YWHAZ to promote hyperactivity. Studies of patient cells were not performed. Drosophila with CRISPR/Cas9-mediated knock-in of the K49N mutation showed significant memory defects on an olfactory test compared to controls, and some abnormal brain structures were observed in the mushroom body. No obvious seizure activity could be elicited with mechanical stimulus in mutant flies. RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila also caused memory defects and hyperactivity, but no seizure activity. There was no difference in cognitive function between ywhaz knockdown flies who were crossed with heterozygous K49N flies, suggesting that the K49N variant is not a gain-of-function variant, but rather results in a loss of function.
Anton-Galindo, E., Dalla Vecchia, E., Orlandi, J. G., Castro, G., Gualda, E. J., Young, A. M. J., Guasch-Piqueras, M., Arenas, C., Herrera-Ubeda, C., Garcia-Fernandez, J., Aguado, F., Loza-Alvarez, P., Cormand, B., Norton, W. H. J., Fernandez-Castillo, N. Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish. Molec. Psychiat. 27: 3739-3748, 2022. [PubMed: 35501409, related citations] [Full Text]
Birkenfeld, J., Kartmann, B., Anliker, B., Ono, K., Schlotcke, B., Betz, H., Roth, D. Characterization of zetin 1/rBSPRY, a novel binding partner of 14-3-3 proteins. Biochem. Biophys. Res. Commun. 302: 526-533, 2003. [PubMed: 12615066, related citations] [Full Text]
Hamosh, A. Personal Communication. Baltimore, Md. 8/27/2025.
Han, L. Wong, D., Dhaka, A., Afar, D., White, M., Xie, W., Herschman, H., Witte, O., Colicelli, J. Protein binding and signaling properties of RIN1 suggest a unique effector function. Proc. Nat. Acad. Sci. 94: 4954-4959, 1997. [PubMed: 9144171, related citations] [Full Text]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/19/2010.
Leffers, H., Madsen, P., Rasmussen, H. H., Honore, B., Andersen, A. H., Walbum, E., Vandekerckhove, J., Celis, J. E. Molecular cloning and expression of the transformation sensitive epithelial marker stratifin: a member of a protein family that has been involved in the protein kinase C signalling pathway. J. Molec. Biol. 231: 982-998, 1993. [PubMed: 8515476, related citations] [Full Text]
Leivonen, S.-K., Rokka, A., Ostling, P., Kohonen, P., Corthals, G. L., Kallioniemi, O., Perala, M. Identification of miR-193b targets in breast cancer cells and systems biological analysis of their functional impact. Molec. Cell. Proteomics 10: M110.005322, 2011. Note: Electronic Article. [PubMed: 21512034, related citations] [Full Text]
Li, Y., Zou, L., Li, Q., Haibe-Kains, B., Tian, R, Li, Y., Desmedt, C., Sotiriou, C., Szallasi, Z, Iglehart, J. D., Richardson, A. L., Wang, Z. C. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nature Med. 16: 214-218, 2010. Note: Editorial Expression of Concern: Nature Med. 31: 4316, 2025. [PubMed: 20098429, related citations] [Full Text]
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. 313: 3624-3634, 2007. [PubMed: 17720156, related citations] [Full Text]
Ogihara, T., Isobe, T., Ichimura, T., Taoka, M., Funaki, M., Sakoda, H., Onishi, Y., Inukai, K., Anai, M., Fukushima, Y., Kikuchi, M., Yazaki, Y., Oka, Y., Asano, T. 14-3-3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain. J. Biol. Chem. 272: 25267-25274, 1997. [PubMed: 9312143, related citations] [Full Text]
Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J. Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature 575: 545-550, 2019. [PubMed: 31581174, related citations] [Full Text]
Popov, I. K., Hiatt, S. M., whalen, S., Keren, B., Ruivenkamp, C., van Haeringen, A., Chen, M.-J., Cooper, G. M., Korf, B. R., Chang, C. A YWHAZ variant associated with cardiofaciocutaneous syndrome activates the RAF-ERK pathway. Front. Physiol. 10: 388, 2019. Note: Electronic Article. [PubMed: 31024343, related citations] [Full Text]
Powell, D. W., Rane, M. J., Chen, Q., Singh, S., McLeish, K. R. Identification of 14-3-3-zeta as a protein kinase B/Akt substrate. J. Biol. Chem. 277: 21639-21642, 2002. [PubMed: 11956222, related citations] [Full Text]
Sun, Y., Peng, J., Liang, D., Ye, X., Xu, N., Chen, L., Yan, D., Zhang, H., Xiao, B., Qiu, W., Shen, Y., Pang, N., and 17 others. Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study. Hum. Mutat. 43: 568-581, 2022. [PubMed: 35143101, related citations] [Full Text]
Tian, Q., Feetham, M. C., Tao, W. A., He, X. C., Li, L., Aebersold, R., Hood, L. Proteomic analysis identifies that 14-3-3-zeta interacts with beta-catenin and facilitates its activation by Akt. Proc. Nat. Acad. Sci. 101: 15370-15375, 2004. [PubMed: 15492215, related citations] [Full Text]
Tommerup, N., Leffers, H. Assignment of the human genes encoding 14-3-3 eta (YWHAH) to 22q12, 14-3-3 zeta (YWHAZ) to 2p25.1-p25.2, and 14-3-3 beta (YWHAB) to 20q13.1 by in situ hybridization. Genomics 33: 149-150, 1996. [PubMed: 8617504, related citations] [Full Text]
Wan, R. P., Liu, Z. G., Huang, X. F., Kwan, P., Li, Y. P., Qu, X. C., Ye, X. G., Chen, F. Y., Zhang, D. W., He, M. F., Wang, J., Mao, Y. L., Qiao, J. D. YWHAZ variation causes intellectual disability and global developmental delay with brain malformation. Hum. Molec. Genet. 32: 462-472, 2023. [PubMed: 36001342, related citations] [Full Text]
Watanabe, M., Isobe, T., Ichimura, T., Kuwano, R., Takahashi, Y., Kondo, H., Inoue, Y. Molecular cloning of rat cDNAs for the zeta and theta subtypes of 14-3-3 protein and differential distributions of their mRNAs in the brain. Molec. Brain Res. 25: 113-121, 1994. [PubMed: 7984035, related citations] [Full Text]
Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H., Gamblin, S. J., Smerdon, S. J., Cantley, L. C. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91: 961-971, 1997. [PubMed: 9428519, related citations] [Full Text]
Zheng, W., Zhang, Z., Ganguly, S., Weller, J. L., Klein, D. C., Cole, P. A. Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nature Struct. Biol. 10: 1054-1057, 2003. [PubMed: 14578935, related citations] [Full Text]
Zupan, L. A., Steffens, D. L., Berry, C. A., Landt, M., Gross, R. W. Cloning and expression of a human 14-3-3 protein mediating phospholipolysis. J. Biol. Chem. 267: 8707-8710, 1992. [PubMed: 1577711, related citations]
Alternative titles; symbols
HGNC Approved Gene Symbol: YWHAZ
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38) : 8:100,916,523-100,953,382 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.3 | Popov-Chang syndrome | 618428 | Autosomal dominant | 3 |
The highly conserved 14-3-3 proteins are found in both plants and mammals. Some have been shown to be involved in the activation of c-Raf (164760) by their participation in the protein kinase C signaling pathway (see 176960). Leffers et al. (1993) reported the cloning of 14-3-3-zeta. See YWHAH (113508) and YWHAB (601289).
Watanabe et al. (1994) isolated the rat zeta isoform of 14-3-3 from rat brain. The deduced 245-amino acid protein shares high sequence homology with other 14-3-3 subtypes. The zeta mRNA was widely expressed in various gray matter brain regions, including the neocortex, hippocampus, caudate-putamen, thalamus, cerebellar cortex, and several brain stem nuclei. A human protein with phospholipase A2 activity was shown to be the zeta subtype of the 14-3-3 protein (Zupan et al., 1992).
By phylogenetic analysis, Anton-Galindo et al. (2022) confirmed the presence of a human YWHAZ ortholog in zebrafish. The zebrafish 14-3-3 protein was most closely related to the human YWHAZ protein. In situ hybridization showed that ywhaz expression was panneuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum.
Crystal Structure
The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997) identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of YWHAZ complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6-angstrom resolution. The authors showed that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD (603167), and Cbl.
Cryoelectron Microscopy
Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF (164757) in complexes with MEK1 (176872) and a 14-3-3 dimer of eta (YWHAH; 113508) and zeta (YWHAZ). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer.
The binding of insulin (176730) to its receptor induces the phosphorylation of the cytosolic substrates IRS1 (147545) and IRS2 (600797), which associate with several Src homology-2 (SH2) domain-containing proteins. To identify unique IRS1-binding proteins, Ogihara et al. (1997) screened a human heart cDNA expression library with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 protein family, 14-3-3-zeta and -epsilon (YWHAE; 605066). 14-3-3 protein has been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells, Chinese hamster ovary cells, and bovine brain tissue. The amount of 14-3-3 protein associated with IRS1 was not affected by insulin stimulation but was increased significantly by treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. The authors identified a putative 14-3-3 protein-binding site within the phosphotyrosine-binding (PTB) domain of IRS1. Ogihara et al. (1997) suggested that the association with 14-3-3 protein may play a role in the regulation of insulin sensitivity by interrupting the association between the insulin receptor and IRS1.
Using 2-hybrid experiments, Han et al. (1997) demonstrated interaction between murine Ywhaz and the RAS-binding domain of RIN1 (605965).
Using in vitro pull-down assays, Powell et al. (2002) showed that recombinant 14-3-3-zeta interacted directly with both recombinant and endogenous protein kinase B (PKB, or AKT1; 164730) within embryonic kidney cell lysates. They found that recombinant PKB phosphorylated 14-3-3-zeta in an in vitro kinase assay, and transfection of active PKB into embryonic kidney cells resulted in phosphorylation of 14-3-3-zeta. By mutation analysis, Powell et al. (2002) determined that the phosphate acceptor was serine-58. They also showed that phosphorylation did not result in 14-3-3-zeta dimerization.
Serotonin N-acetyltransferase (AANAT; 600950) controls daily changes in the production and circulating levels of melatonin. Zheng et al. (2003) studied the significance of the phosphorylation of AANAT using a semisynthetic enzyme in which a nonhydrolyzable phosphoserine/threonine mimetic, phosphonomethylenealanine (Pma), was incorporated at position 31 (AANAT-Pma31). The results of studies in which AANAT-Pma31 and related analogs were injected into cells provided the first evidence that threonine-31 phosphorylation controls AANAT stability in the context of the intact cells by binding to 14-3-3-zeta protein. Zheng et al. (2003) concluded that their findings established threonine-31 phosphorylation as an essential element in the intracellular regulation of melatonin production.
Using a yeast 2-hybrid screen, Birkenfeld et al. (2003) identified rat zetin-1 (BSPRY; 619683) as an interacting partner of the zeta isoform of 14-3-3 proteins. Immunoprecipitation and immunocytochemical analyses revealed that the 2 proteins interacted and colocalized in transfected COS-7 cells.
By coimmunoprecipitation and tandem mass spectrometric analysis, Tian et al. (2004) found that 14-3-3-zeta is a beta-catenin (116806)-interacting protein. 14-3-3-zeta enhanced beta-catenin-dependent transcription by stabilizing beta-catenin in the cytoplasm. Furthermore, 14-3-3-zeta facilitated activation of beta-catenin by AKT and colocalized with activated Akt in mouse intestinal stem cells. Tian et al. (2004) proposed that AKT phosphorylates beta-catenin, leading to 14-3-3-zeta binding and stabilization of beta catenin.
Li et al. (2010) found a significant association between amplification of a region on chromosome 8q22 and de novo chemoresistance to anthracyclines and metastatic recurrence in human breast cancer (114480). Within this region, overexpression of both the YWHAZ and LAPTM4B (613296) genes was found to correlate with the observations. Knockdown of either of these genes using siRNA resulting in sensitivity of tumor cells to anthracyclines. Extensive in vitro studies confirmed the effect. Further studies indicated that LAPTM4B resulted in sequestration of anthracycline and delayed entry into the nucleus, whereas YWHAZ likely protected cells from apoptosis. The findings were specific to anthracyclines. An Editorial Expression of Concern was published for the article of Li et al. (2010).
Using proteomics and mass spectrometric analysis, Leivonen et al. (2011) identified 14-3-3-zeta, SHMT2 (138450), and AKR1C2 (600450) as major targets of microRNA-193B (MIR193B; 614734) in MCF-7 human breast cancer cells. Cotransfection experiments confirmed that MIR193B downregulated expression of reporter genes containing the 3-prime UTRs of SHMT2 or YWHAZ or the 5-prime UTR of AKR1C2. Neutralization of MIR193B with anti-MIR193B led to elevated SHMT2 and AKR1C2 protein levels, with lesser upregulation of YWHAZ protein. Specific combinations of knockdowns of these target genes via small interfering RNAs inhibited growth in MCF-7 cells.
By coimmunoprecipitation analysis of HeLa cell lysates, Mizuno et al. (2007) showed that the 14-3-3 proteins YWHAE, YWHAG (605356), and YWHAZ bound mouse Usp8 (603158). Binding of 14-3-3 proteins to Usp8 was inhibited by phosphatase treatment, by mutating the consensus 14-3-3-binding motif in Usp8, or by competition with a phosphorylated 14-3-3-binding peptide. The authors identified ser680 within the 14-3-3-binding motif as the major phosphorylation site of mouse Usp8. Mutation of ser680 led to enhanced ubiquitin isopeptidase activity of Usp8 against polyubiquitin chains and human EGFR (131550). Addition of mouse Ywhae inhibited USP8 activity. Usp8 was dephosphorylated at ser680 and dissociated from 14-3-3 proteins in M phase, resulting in enhanced Usp8 activity during cell division. Mizuno et al. (2007) concluded that USP8 is catalytically inhibited in a phosphorylation-dependent manner by 14-3-3 proteins during interphase and that the regulation is discontinued in M phase.
Tommerup and Leffers (1996) mapped the YWHAZ gene to chromosome 2p25.2-p25.1 by fluorescence in situ hybridization. However, Hartz (2010) mapped the YWHAZ gene to chromosome 8q22.3 based on an alignment of the YWHAZ sequence (GenBank BC003623) with the genomic sequence (GRCh37).
In 5 unrelated patients with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified 5 different de novo heterozygous mutations in the YWHAZ gene (601288.0001-601288.0005), including 3 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. The first patient was identified through a genome sequencing research study, and the other 4 patients were subsequently identified through GeneMatcher or through data-sharing of exome sequencing. Detailed functional studies of 1 of the missense variants (S230W; 601288.0001) in Xenopus indicated that this mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway (see ANIMAL MODEL). Functional studies of the other YWHAZ variants and studies of patient cells were not performed. Of note, the patient (P1) with the S230W mutation also carried a heterozygous frameshift variant (c.4022_4023insGA) in the SCN8A gene (600702); heterozygous mutation in the SCN8A gene is associated with several neurologic disorders (see, e.g., CIAT, 614306). Patient 4 (see 601288.0004) also carried a de novo heterozygous frameshift variant (c.522_523insC) in the MAP3K14 gene (604655).
In a Chinese boy (proband) and his father (family WGS1059JH) with POPCHAS, Sun et al. (2022) identified a heterozygous missense mutation in the YWHAZ gene (E14K; 601288.0006). Functional studies of the variant were not performed. The proband was part of a cohort of 100 pediatric patients with global developmental delay/intellectual disability who underwent whole-genome sequencing. Hamosh (2025) noted that the E14K variant was not present in the gnomAD database (v4.1.0).
In 7 affected individuals spanning 3 generations of a family with POPCHAS, Wan et al. (2023) identified a heterozygous missense mutation in the YWHAZ gene (K49N; 601288.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including 1000 Genomes Project, Exome Sequencing Project, ExAC, and gnomAD. Studies of patient cells were not performed. Drosophila with CRISPR/Cas9-mediated knock-in of the K49N mutation showed significant memory defects on an olfactory test compared to controls, and some abnormal brain structures were observed in the mushroom body. No obvious seizure activity could be elicited with mechanical stimulus in mutant flies. RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila also caused memory defects and hyperactivity, but no seizure activity. There was no difference in cognitive function between ywhaz knockdown flies who were crossed with heterozygous K49N flies, suggesting that the K49N variant is not a gain-of-function variant, but rather results in a loss of function.
Popov et al. (2019) found that injection of the S230W mutation into Xenopus embryos caused dark pigmentation, possibly reflecting changes in cell shape, as well as defects in head structure and shortened and bent body axis compared to controls. The abnormalities induced by the mutant gene were more severe than those induced by overexpression of the wildtype gene. Further studies showed that the mutant Ywhaz protein was able to rescue defects induced by dominant-negative Fgfr1 (136350) and stimulated Raf-dependent Erk phosphorylation more efficiently than wildtype, consistent with a gain of function.
Wan et al. (2023) found that RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila caused memory defects and hyperactivity, but no seizure activity.
In a 9-year-old boy (patient 1) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.689C-G transversion (c.689C-G, NM_145690.2) in the YWHAZ gene, resulting in a ser230-to-trp (S230W) substitution in helix 6. The mutation, which was found by trio-based whole-genome sequencing, was not present in the gnomAD database. Detailed functional expression studies in Xenopus indicated that the S230W mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway compared to wildtype. Studies of patient cells were not performed. The patient also carried a heterozygous frameshift variant (c.4022_4023insGA) in the SCN8A gene (600702); heterozygous mutation in the SCN8A gene is associated with several neurologic disorders (see, e.g., CIAT, 614306).
In a 12-year-old girl (patient 2) with Popov-Change syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.157G-A transition (c.157G-A, NM_145690.2) in the YWHAZ gene, resulting in a gly53-to-arg (G53R) substitution in helix 3, which is involved in protein dimerization and ligand binding. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 17-year-old girl (patient 3) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.40G-T Popov et al. (2019) identified a de novo heterozygous c.434C-T transition (c.434C-T, NM_145690.2) in the YWHAZ gene, resulting in a ser145-to-leu (S145L) substitution in helix 6. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 9-year-old girl (patient 4) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous c.40G-T transversion (c.40G-T, NM_145690.2) in the YWHAZ gene, resulting in a glu14-to-ter (E14X) substitution. The variant was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient also carried a de novo heterozygous frameshift variant (c.522_523insC) in the MAP3K14 gene (604655).
In a 17-year-old boy (patient 5) with Popov-Chang syndrome (POPCHAS; 618428), Popov et al. (2019) identified a de novo heterozygous 2-bp insertion (c.688_689insAT, NM_145690.2) in the YWHAZ gene, resulting in a frameshift and premature termination (Ser230TyrfsTer44). The mutation was found by trio-based exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
Anton-Galindo et al. (2022) found that ywhaz -/- zebrafish larvae displayed altered spontaneous neuronal activity and functional connectivity in the hindbrain. Adult ywhaz -/- fish displayed decreased levels of monoamines in the hindbrain and froze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. RT-PCR analysis revealed that loss of ywhaz function altered the expression of genes involved in the dopaminergic and serotonergic pathways.
In a Chinese boy (proband) and his father (family WGS1059GH) with Popov-Chang syndrome (POPCHAS; 618428), Sun et al. (2022) identified a heterozygous c.40G-A transition in the YWHAZ gene, resulting in a glu14-to-lys (E14K) substitution. The mutation appeared to occur de novo in the father, since it was not found in his unaffected parents. Functional studies of the variant were not performed. The boy (proband) was part of a cohort of 110 pediatric Chinese patients with global developmental delay who underwent whole-genome sequencing. Hamosh (2025) noted that the E14K variant was not present in the gnomAD database (v4.1.0).
In 7 affected individuals spanning 3 generations of a family with Popov-Chang syndrome (POPCHAS; 618428), Wan et al. (2023) identified a heterozygous c.147A-T transversion (c.147A-T, NM_001135699.1) in the YWHAZ gene, resulting in a lys49-to-asn (K49N) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including 1000 Genomes Project, Exome Sequencing Project, ExAC, and gnomAD. The authors stated in the text that 4 affected family members with hyperactivity/irritability also carried variants in 4 other genes (ARHGAP4, AGPS, APOL3, and KREMEN1), suggesting that these genes may be associated with hyperactivity or interact with YWHAZ to promote hyperactivity. Studies of patient cells were not performed. Drosophila with CRISPR/Cas9-mediated knock-in of the K49N mutation showed significant memory defects on an olfactory test compared to controls, and some abnormal brain structures were observed in the mushroom body. No obvious seizure activity could be elicited with mechanical stimulus in mutant flies. RNAi-mediated homozygous knockdown of the ywhaz gene in Drosophila also caused memory defects and hyperactivity, but no seizure activity. There was no difference in cognitive function between ywhaz knockdown flies who were crossed with heterozygous K49N flies, suggesting that the K49N variant is not a gain-of-function variant, but rather results in a loss of function.
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