Affinage

YWHAQ

14-3-3 protein theta · UniProt P27348

Round 2 corrected
Length
245 aa
Mass
27.8 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YWHAQ (14-3-3 theta/tau) is a phosphoserine/phosphothreonine-binding adaptor protein that recognizes RSXpSXP and RXY/FXpSXP consensus motifs on client proteins, functioning as a central integrator of phosphorylation-dependent signaling across survival, cell cycle, metabolic, and cytoskeletal pathways (PMID:8601312, PMID:9428519). By binding phosphorylated clients—including BAD, FOXO3a, YAP, HDAC4/5, CDC25B, TORC2, raptor, SIKs, IRSp53, and hTERT—it controls their subcellular localization through cytoplasmic retention or modulation of CRM1-dependent nuclear export, thereby gating transcription factor activity, apoptotic effector deployment, and mTORC1 signaling (PMID:8929531, PMID:10835362, PMID:10958686, PMID:18439900). 14-3-3 dimers achieve high-affinity bidentate engagement of tandem phosphorylation sites on single client molecules, and this multivalent binding is itself regulated by stress kinases such as JNK, which phosphorylate 14-3-3 to trigger client release and apoptotic pathway activation (PMID:9428519, PMID:30696821, PMID:15071501). Additionally, 14-3-3 theta directly activates tryptophan and tyrosine hydroxylases upon phosphorylation-dependent binding and bridges misfolded protein cargo to dynein motors for aggresome transport (PMID:9334190, PMID:10569954, PMID:24549097).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    The first functional link between 14-3-3 and a kinase cascade was established when 14-3-3 isoforms were shown to bind the Raf-1 N-terminus and activate Raf-1-dependent signaling, positioning 14-3-3 as a signaling adaptor rather than merely a brain-abundant protein.

    Evidence Yeast two-hybrid identification plus Xenopus oocyte Raf-1-dependent maturation assay with dominant-negative rescue

    PMID:7935795

    Open questions at the time
    • Binding mechanism (phosphorylation dependence) not yet identified
    • Isoform specificity for Raf-1 interaction not resolved
  2. 1996 High

    The core recognition mechanism of 14-3-3 proteins was defined as phosphoserine binding, with consensus motifs identified on Raf-1 and other partners; simultaneously, phosphorylation-dependent sequestration of BAD by 14-3-3 established cytoplasmic retention as a functional paradigm for controlling apoptosis.

    Evidence Phosphopeptide competition assays disrupting 14-3-3 complexes (Cell, 1996); co-IP, phospho-site mutagenesis, and subcellular fractionation showing BAD sequestration (Cell, 1996)

    PMID:8601312 PMID:8929531

    Open questions at the time
    • Structural basis of phosphoserine recognition not yet solved
    • Whether cytoplasmic retention mechanism extends beyond BAD
  3. 1996 Medium

    YWHAQ (14-3-3 tau) was specifically shown to associate with Cbl in activated T cells, with its C-terminal 15 residues required for binding Cbl, Raf-1, and PI3-K, suggesting that 14-3-3 tau coordinates multiple signaling partners simultaneously.

    Evidence Co-immunoprecipitation in vitro and in vivo in T cells with truncated fusion protein mapping

    PMID:8663231

    Open questions at the time
    • Reciprocal validation with endogenous Cbl limited
    • Functional consequence of 14-3-3 tau–Cbl interaction on T cell signaling not determined
  4. 1997 High

    Crystal structure of 14-3-3 zeta bound to a phosphoserine peptide revealed the amphipathic groove as the binding channel and defined two consensus motifs (RSXpSXP and RXY/FXpSXP), explaining bidentate engagement of tandem phosphosites on clients like Raf and BAD.

    Evidence X-ray crystallography at 2.6 Å combined with phosphoserine-oriented peptide library screening

    PMID:9428519

    Open questions at the time
    • Structure solved for zeta isoform; whether theta groove geometry differs not addressed
    • Co-crystal with full-length client protein not achieved
  5. 1997 High

    14-3-3 binding to phosphorylated tryptophan hydroxylase was shown to directly activate the enzyme and protect it from dephosphorylation, establishing that 14-3-3 can allosterically regulate enzymatic activity beyond simply altering localization.

    Evidence In vitro reconstitution with surface plasmon resonance (Kd ~3 nM), enzymatic activity assay, and dephosphorylation protection assay

    PMID:9334190

    Open questions at the time
    • In vivo relevance of TPH activation by 14-3-3 not demonstrated in neurons
    • Isoform specificity for hydroxylase activation unclear
  6. 1999 High

    Extension of the enzymatic activation paradigm to tyrosine hydroxylase demonstrated that stimulus-dependent CaM kinase II phosphorylation at Ser-19 recruits 14-3-3 to activate catecholamine synthesis in PC12 cells, linking 14-3-3 to neurotransmitter biosynthesis.

    Evidence Baculovirus-expressed TH, Ser19Ala mutagenesis, phosphopeptide competition, cell depolarization in PC12 cells

    PMID:10569954

    Open questions at the time
    • In vivo significance in dopaminergic neurons not established
    • Whether 14-3-3 theta versus other isoforms preferentially activates TH
  7. 2000 High

    14-3-3 was shown to regulate nucleocytoplasmic trafficking: it promotes nuclear retention of hTERT by blocking CRM1-mediated export, and mediates cytoplasmic sequestration of HDAC4 by binding three phosphoserines, establishing 14-3-3 as a bidirectional regulator of nuclear–cytoplasmic partitioning.

    Evidence Dominant-negative 14-3-3 and hTERT-3A mutant with leptomycin B treatment (EMBO J); HDAC4 phospho-site triple alanine mutagenesis with localization and reporter assays (MCB)

    PMID:10835362 PMID:10958686

    Open questions at the time
    • Whether 14-3-3 theta specifically mediates hTERT nuclear retention or all isoforms function equivalently
    • Structural basis of HDAC4–14-3-3 complex not resolved
  8. 2001 High

    14-3-3 binding to CDC25B at Ser323 was found to directly inhibit phosphatase activity by blocking substrate access, providing the first case where 14-3-3 inhibits catalytic function through steric occlusion rather than relocalization, and linking 14-3-3 to G2/M checkpoint enforcement.

    Evidence S323A mutagenesis in G2-arrested cells with cyclin B/cdc2 kinase assay and cell cycle analysis

    PMID:11466620

    Open questions at the time
    • Whether the steric blockade mechanism applies to other 14-3-3–phosphatase interactions
    • Isoform preference for CDC25B binding not tested
  9. 2002 Medium

    14-3-3 was placed downstream of Akt in mTOR pathway regulation when Akt-dependent phosphorylation of TSC2 at Ser1210 was shown to create a 14-3-3 binding site, potentially inactivating the TSC1–TSC2 tumor suppressor complex.

    Evidence In vivo co-immunoprecipitation with Ser1210 mutagenesis

    PMID:12364343

    Open questions at the time
    • Functional consequence of 14-3-3 binding on TSC2 GAP activity not directly measured
    • Contribution of individual 14-3-3 isoforms to TSC2 regulation not determined
  10. 2002 High

    The nucleocytoplasmic shuttling mechanism was refined: 14-3-3 and CRM1 were shown to operate via non-overlapping mechanisms to jointly sequester FKHRL1/FOXO3a in the cytoplasm, with phosphorylation occurring in the nucleus immediately before export.

    Evidence GFP-fusion live imaging, nuclear fractionation, leptomycin B, C-terminal 14-3-3 mutants

    PMID:11864996

    Open questions at the time
    • Whether 14-3-3 accompanies FOXO3a during transit through nuclear pores not resolved
    • Kinase responsible for nuclear phosphorylation of FOXO3a at 14-3-3 sites not identified in this study
  11. 2003 Medium

    14-3-3 tau (YWHAQ) was linked to extracellular matrix signaling when tenascin-C was shown to induce its expression, and overexpression of 14-3-3 tau normalized F-actin organization and promoted cell adhesion/survival on tenascin-C substrates.

    Evidence cDNA subtraction screen, stable overexpression, F-actin immunofluorescence, adhesion/growth assays in MCF-7, fibrosarcoma, and glioblastoma cells

    PMID:12527748

    Open questions at the time
    • Direct binding partners mediating 14-3-3 tau effects on cytoskeleton in this context not identified
    • Mechanism of tenascin-C-induced YWHAQ transcription unknown
  12. 2003 High

    Akt-mediated phosphorylation of YAP at Ser127 was shown to create a 14-3-3 binding site causing YAP cytoplasmic sequestration, thereby suppressing p73-dependent apoptotic transcription—a mechanism later recognized as central to Hippo pathway output.

    Evidence Affinity purification of Akt substrates, co-IP, subcellular fractionation, p73 reporter, apoptosis assay

    PMID:12535517

    Open questions at the time
    • Contribution of specific 14-3-3 isoforms to YAP regulation not dissected
    • Whether 14-3-3 binding alters YAP protein stability not addressed
  13. 2004 High

    14-3-3 was identified as a coincidence detector integrating calcium and cAMP pathways: under resting conditions it sequesters TORC2 in the cytoplasm; calcineurin and SIK2 inhibition converge to release TORC2 for nuclear CREB activation.

    Evidence Co-IP, subcellular fractionation, phosphatase activity assays, kinase inhibition, reporter gene assays

    PMID:15454081

    Open questions at the time
    • Whether TORC2–14-3-3 complex stoichiometry involves bidentate or monovalent binding not structurally resolved
  14. 2004 High

    JNK-mediated phosphorylation of 14-3-3 itself (Ser184 on zeta) was discovered to release pro-apoptotic clients Bax and Bad, establishing that 14-3-3 is not merely a passive scaffold but an active signaling node regulated by stress kinases.

    Evidence Phosphorylation-defective 14-3-3 mutant blocking Bax translocation, cytochrome c release, and apoptosis; extended to Bad and FOXO3a release

    PMID:15071501 PMID:16009721

    Open questions at the time
    • Whether JNK phosphorylates 14-3-3 theta at the equivalent site not directly tested
    • In vivo confirmation of JNK–14-3-3 axis in animal models not reported
  15. 2006 High

    14-3-3 was shown to terminate NF-κB signaling by facilitating nuclear export of IκBα–p65 complexes, with dominant-negative 14-3-3 causing constitutive p65 chromatin association and loss of TNFα-responsive gene regulation.

    Evidence Domain mapping, dominant-negative 14-3-3, ChIP, subcellular localization, reporter assays

    PMID:16931600

    Open questions at the time
    • Which 14-3-3 isoform(s) are physiologically responsible for NF-κB termination not resolved
    • Phosphorylation sites on p65/IκBα mediating 14-3-3 binding not fully mapped
  16. 2008 High

    14-3-3 was positioned as an effector of metabolic checkpoint control when AMPK-mediated phosphorylation of raptor was shown to require 14-3-3 binding for mTORC1 inhibition and energy-stress-induced cell-cycle arrest.

    Evidence In vitro AMPK kinase assay, raptor phospho-site mutagenesis, 14-3-3 binding assay, mTORC1 and cell-cycle readouts

    PMID:18439900

    Open questions at the time
    • Whether 14-3-3 binding disrupts raptor–mTOR interaction or alters raptor localization not mechanistically distinguished
  17. 2009 High

    Structural and biophysical studies revealed multivalent engagement principles: crystal structures of 14-3-3 with diphosphorylated PKCε and IRSp53 showed that tandem phosphosite engagement on a single client dramatically enhances binding affinity and enables conformational regulation (demonstrated by FRET sensors for IRSp53).

    Evidence X-ray crystallography of 14-3-3–PKCε and 14-3-3–IRSp53 complexes, ITC, SPR, FRET conformational sensor, membrane binding assay

    PMID:19662078 PMID:30696821

    Open questions at the time
    • Full-length client–14-3-3 co-crystal structures not yet solved
    • Whether conformational change mechanism generalizes to other clients unknown
  18. 2009 High

    14-3-3 binding was found to regulate mRNA stability by sequestering the decay factor KSRP in the nucleus after phosphorylation-induced KH1 domain unfolding, connecting extracellular signaling to post-transcriptional gene regulation.

    Evidence NMR of KSRP KH1 domain, phosphorylation-dependent binding, subcellular localization, ARE-mRNA decay assay

    PMID:19198587

    Open questions at the time
    • Identity of kinase phosphorylating KSRP KH1 in physiological context not fully defined
    • Global impact on ARE-mRNA transcriptome not assessed
  19. 2018 High

    PKA-dependent phosphorylation of all three SIK family kinases was shown to create 14-3-3 binding sites that directly inhibit SIK catalytic activity, establishing 14-3-3 as the mediator of cAMP-dependent SIK inactivation with implications for CREB, HDAC, and metabolic regulation.

    Evidence Co-IP, kinase activity assay, phospho-site mutagenesis across SIK1/2/3, cAMP stimulation

    PMID:29211348

    Open questions at the time
    • Isoform specificity of 14-3-3 for SIK binding not tested
    • In vivo tissue-specific consequences of SIK–14-3-3 disruption not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether individual 14-3-3 isoforms (particularly theta versus other family members) have non-redundant client specificities in vivo; the structural basis of full-length client recognition by 14-3-3 theta dimers; and how cells coordinate the release of multiple clients from a shared 14-3-3 pool under competing kinase inputs.
  • No isoform-specific knockout phenotype reported for YWHAQ in vivo
  • No full-length client co-crystal structure with any 14-3-3 isoform
  • Systems-level modeling of competitive client binding to the 14-3-3 pool not attempted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 9 GO:0098772 molecular function regulator activity 5
Localization
GO:0005829 cytosol 5 GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-5357801 Programmed Cell Death 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 3
Partners
BADBAIAP2CDC25BCRTC2HDAC4LRRK2RPTORYAP1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 14-3-3 proteins (including tau/theta) function as specific phosphoserine-binding proteins; a consensus binding motif on Raf-1 and other known 14-3-3 partners was defined, and phosphopeptides containing this motif could disrupt 14-3-3 complexes and inhibit Xenopus oocyte maturation, establishing phosphoserine recognition as the core mechanism of 14-3-3 interaction with signaling proteins. Phosphopeptide binding assays, co-immunoprecipitation, Xenopus oocyte functional assay Cell High 8601312
1997 Crystal structure of 14-3-3 zeta complexed with a phosphoserine motif (from polyoma middle-T) at 2.6 Å resolution revealed that the bound peptide adopts an extended conformation with a tight turn created by the pS+2 Pro in cis conformation; the 14-3-3 dimer binds tightly to single molecules containing tandem phosphoserine motifs via bidentate association, implicating this mechanism for Raf, BAD, and Cbl regulation. Two distinct binding motifs (RSXpSXP and RXY/FXpSXP) were identified across all mammalian and yeast 14-3-3 isoforms. Phosphoserine-oriented peptide libraries, X-ray crystallography (2.6 Å) Cell High 9428519
1994 14-3-3 zeta and 14-3-3 beta interact with the amino-terminal region of Raf-1 (identified by yeast two-hybrid), and expression of 14-3-3 proteins in Xenopus oocytes enhanced Raf-1 kinase activity and promoted Raf-1-dependent oocyte maturation; a dominant-negative Raf-1 blocked these effects, establishing 14-3-3 as an activator of Raf-1 in signal transduction. Yeast two-hybrid, Xenopus oocyte functional assay, dominant-negative analysis Nature High 7935795
1996 14-3-3 tau (YWHAQ) associates with Cbl (a 120 kDa tyrosine-phosphorylated protein) in T cells; this interaction was markedly increased following T cell activation and detected both in vitro and in intact cells. The 15 C-terminal residues of 14-3-3 tau are required for association with Cbl, Raf-1, and PI3-K, suggesting 14-3-3 dimers coordinate protein–protein interactions of multiple signaling proteins simultaneously. Co-immunoprecipitation (in vitro and in vivo), truncated fusion protein binding assays The Journal of biological chemistry Medium 8663231
1996 14-3-3 proteins (epsilon and gamma isoforms) associate specifically with centrosomes and the spindle apparatus as detected by immunofluorescence and centrosome isolation by sucrose density gradient; this centrosomal localization is serum-dependent (absent in quiescent cells, restored upon serum stimulation), linking 14-3-3 to mitogenic signaling at the centrosome. Immunofluorescence microscopy, centrosome isolation by sucrose density gradient centrifugation, immunoblotting Blood cells, molecules & diseases Medium 9075573
1996 14-3-3 proteins were found in neurofibrillary tangles (NFT) of Alzheimer's disease brains by immunohistochemistry; NFT stained by anti-14-3-3 were smaller and more confined to the neuronal cell body than those stained by anti-tau or anti-ubiquitin, supporting involvement of 14-3-3 in MAP kinase signalling leading to tau hyperphosphorylation. Immunohistochemistry with isoform-specific antibodies, double-labeling Neuroscience letters Low 8734909
1997 14-3-3 proteins bind to phosphorylated tryptophan hydroxylase (TPH) at the cAMP-dependent protein kinase phosphorylation site; this binding activates TPH activity by ~45% and inhibits its dephosphorylation by protein phosphatase-1. The interaction is phosphorylation-dependent with a Kd ~3 nM as measured by surface plasmon resonance. In vitro binding assay, affinity chromatography, surface plasmon resonance, enzymatic activity assay The Journal of biological chemistry High 9334190
1996 Serine phosphorylation of the pro-apoptotic protein BAD in response to survival factor IL-3 causes it to bind 14-3-3 and become sequestered in the cytosol; only non-phosphorylated BAD heterodimerizes with BCL-XL at mitochondrial membranes to promote cell death, establishing 14-3-3 binding as a cytoplasmic retention mechanism that neutralizes BAD's death-promoting activity. Co-immunoprecipitation, phosphorylation site mutagenesis, subcellular fractionation Cell High 8929531
1999 14-3-3 proteins bind to tyrosine hydroxylase (TH) phosphorylated at Ser-19 by CaM kinase II; this binding activates TH enzymatic activity and occurs in PC12 cells in response to depolarization-induced Ca2+ influx, linking stimulus-dependent phosphorylation of TH to 14-3-3-mediated activation of catecholamine synthesis. The complex has Kd of ~3 nM and is blocked by a phosphopeptide corresponding to the phosphoSer-19 site. Baculovirus-expressed TH, co-immunoprecipitation, site-directed mutagenesis (Ser-19→Ala), synthetic phosphopeptide competition, in vitro enzymatic assay, cell stimulation Biochemistry High 10569954
2000 14-3-3 proteins interact with hTERT (human telomerase catalytic subunit) and promote its nuclear localization by inhibiting CRM1/exportin-1-mediated nuclear export; a dominant-negative 14-3-3 or a 14-3-3-binding-defective hTERT mutant (hTERT-3A) redistributed hTERT to the cytoplasm with increased CRM1 association. 14-3-3 binding was not required for telomerase enzymatic activity itself. Dominant-negative 14-3-3 expression, hTERT-3A mutant, subcellular fractionation, co-immunoprecipitation, leptomycin B treatment, telomerase activity assay The EMBO journal High 10835362
2000 14-3-3 proteins regulate HDAC4 subcellular localization by binding to phosphoserine residues (S246, S467, S632); alanine substitution of these serines abolished 14-3-3 binding and stimulated HDAC4 nuclear localization, leading to enhanced transcriptional repression, without affecting intrinsic deacetylase activity. This demonstrates that 14-3-3 negatively regulates HDAC4 function by cytoplasmic retention. Co-immunoprecipitation, alanine mutagenesis of phosphoserine sites, subcellular localization (immunofluorescence), transcriptional reporter assays, deacetylase activity assay Molecular and cellular biology High 10958686
2001 14-3-3 binding to CDC25B at S323 directly inhibits CDC25B phosphatase activity by blocking substrate (cyclin/CDK) access to the catalytic site; mutation of S323 or removal of the N-terminal regulatory domain strongly activates CDC25B and enables it to overcome G2 checkpoint arrest and induce aberrant mitosis, providing direct mechanistic evidence that 14-3-3 binding controls CDC25B-mediated entry into mitosis. Site-directed mutagenesis (S323A), overexpression in G2-arrested cells, cyclin B/cdc2 kinase assay, cell cycle analysis Oncogene High 11466620
2001 14-3-3 eta and epsilon isoforms were identified as binding partners of p190RhoGEF through yeast two-hybrid screening, confirmed by biochemical co-immunoprecipitation and co-localization in neuronal cells; a phosphorylation-independent binding site (I1370QAIQNL) was mapped in p190RhoGEF, and deletion of this site abolished both the interaction and the ability of 14-3-3 eta to alter cytoplasmic aggregation of p190RhoGEF. Yeast two-hybrid, co-immunoprecipitation, co-localization in transfected neuronal cells, deletion mapping The Journal of biological chemistry Medium 11533041
2002 14-3-3 proteins interact with Bcl-2 family members BAD and ASK1 in a phosphoserine-dependent manner to suppress their pro-apoptotic functions; expression of 14-3-3 antagonist peptides in cells is sufficient to induce apoptosis and can sensitize cells to cisplatin, establishing that 14-3-3 constitutively supports cell survival by sequestering proapoptotic proteins. Co-immunoprecipitation, antagonist peptide expression, cell death assays Biochemical Society transactions Medium 12196095
2002 14-3-3 proteins bind TSC2 (tuberin) in vivo; phosphorylation of Ser1210 in TSC2 (an Akt phosphorylation site) is required for this association; 14-3-3 binding may inhibit TSC2 function, providing a mechanism by which Akt-mediated phosphorylation negatively regulates the TSC1–TSC2 tumor suppressor complex. Co-immunoprecipitation in vivo, phosphorylation site mutagenesis (Ser1210) The Journal of biological chemistry Medium 12364343
2002 14-3-3 and CRM1/exportin-1 act via non-overlapping NES-independent mechanisms to jointly ensure cytoplasmic sequestration of FKHRL1 after 14-3-3 binding; phosphorylation of FKHRL1 at 14-3-3 binding sites occurs in the nucleus immediately before cytoplasmic relocalization; the leucine-rich C-terminal region of 14-3-3 functions in ligand binding rather than as a direct NES, revealing that 14-3-3 participates in dynamic nucleocytoplasmic transport of transcription factors. GFP-fusion live imaging, nuclear fractionation, leptomycin B treatment, 14-3-3 C-terminal mutants, dominant-negative 14-3-3 The Journal of cell biology High 11864996
2003 Tenascin-C matrix signaling induces elevated 14-3-3 tau (YWHAQ) expression; overexpression of 14-3-3 tau in MCF-7 cells altered cell morphology on tenascin-C substrates (cells became flat), normalized F-actin organization, and increased cell growth rate on tenascin-C; ectopic 14-3-3 tau also conferred adhesion and survival of fibrosarcoma and glioblastoma cells on tenascin-C. cDNA subtraction screen, stable and transient transfection overexpression, immunofluorescence (F-actin), cell adhesion and growth assays The Journal of cell biology Medium 12527748
2004 Activated JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 (at Ser184 of 14-3-3 zeta), causing dissociation of the 14-3-3–Bax complex; expression of phosphorylation-defective 14-3-3 mutants blocked JNK-induced Bax translocation, cytochrome c release, and apoptosis, revealing that JNK-mediated phosphorylation of 14-3-3 releases Bax from cytoplasmic anchoring. Phosphorylation-defective 14-3-3 mutant expression, subcellular fractionation, cytochrome c release assay, apoptosis assay, co-immunoprecipitation The EMBO journal High 15071501
2004 14-3-3 proteins (HDAC5 as substrate) are phosphorylated by protein kinase D (PKD), a downstream effector of PKC, at two sites triggering CRM1-dependent nuclear export of class IIA HDAC5; a non-phosphorylatable HDAC5 mutant blocked PKC/PKD-induced nuclear export and cardiomyocyte hypertrophy, establishing a PKC→PKD→14-3-3-binding-mediated nuclear export pathway for HDAC5 in cardiac hypertrophy. In vitro kinase assay, non-phosphorylatable HDAC5 mutant expression, nuclear export assay, cardiomyocyte hypertrophy assay Molecular and cellular biology High 15367659
2005 JNK-mediated phosphorylation of 14-3-3 zeta at Ser184 releases proapoptotic proteins Bad and FOXO3a from 14-3-3, antagonizing Akt survival signaling; released Bad is dephosphorylated and translocates to mitochondria to associate with Bcl-2/Bcl-xL. This establishes 14-3-3 as an integration point between pro-survival (Akt) and pro-apoptotic (JNK) kinase pathways. Co-immunoprecipitation, subcellular fractionation, phosphorylation site mutagenesis, apoptosis assays The Journal of cell biology High 16009721
2006 14-3-3 proteins physically interact with p65 (at residues 38–44 and 278–283) and IκBα (residues 60–65); dominant-negative 14-3-3 causes nuclear accumulation of p65–IκBα complexes and constitutive chromatin association of p65, rendering NFκB-dependent genes unresponsive to TNFα; TNFα treatment promotes 14-3-3 and IκBα recruitment to NFκB promoters, establishing that 14-3-3 facilitates nuclear export of IκBα–p65 complexes to terminate NFκB signaling. Domain mapping by mutagenesis, dominant-negative 14-3-3, chromatin immunoprecipitation, subcellular localization, reporter gene assays Journal of cell science High 16931600
2008 AMPK directly phosphorylates the mTOR binding partner raptor on two conserved serines, and this phosphorylation induces 14-3-3 binding to raptor, which is required for inhibition of mTORC1 and cell-cycle arrest induced by energy stress, placing 14-3-3 as a downstream effector of AMPK-mediated metabolic checkpoint control. In vitro AMPK kinase assay, 14-3-3 binding assay, mTORC1 activity assay, raptor phospho-site mutagenesis, cell-cycle analysis under energy stress Molecular cell High 18439900
2003 Akt phosphorylates Yes-associated protein (YAP) at serine 127, inducing 14-3-3 binding and cytoplasmic relocalization of YAP, thereby attenuating its function as a transcriptional coactivator of p73 and suppressing p73-mediated apoptotic gene expression (including Bax induction) following DNA damage. Affinity purification of Akt substrates, co-immunoprecipitation, subcellular fractionation, p73 transcription reporter assay, apoptosis assay, YAP knockdown/overexpression Molecular cell High 12535517
2004 14-3-3 proteins are recruited to the TORC2 (CREB coactivator) and sequester it in the cytoplasm via phosphorylation-dependent interaction under resting conditions; activation of calcium (via calcineurin) and cAMP (via SIK2 inhibition) pathways disrupts TORC2:14-3-3 complexes and allows TORC2 nuclear entry to activate CREB target genes, establishing 14-3-3 as a coincidence detector integrating two signaling pathways. Co-immunoprecipitation, subcellular fractionation, phosphatase activity assays, kinase inhibition, reporter gene assays Cell High 15454081
2009 Phosphorylation of KSRP within its N-terminal KH1 domain causes unfolding of KH1, creating a 14-3-3 zeta binding site; 14-3-3 zeta binding drives nuclear localization of KSRP and sequesters it in a separate functional pool, impairing its ability to promote mRNA degradation of ARE-containing transcripts, thereby connecting extracellular signaling to mRNA stability regulation. NMR spectroscopy, phosphorylation-dependent binding assays, subcellular localization, mRNA decay assay Nature structural & molecular biology High 19198587
2009 Crystal structure of 14-3-3 zeta bound to a synthetic diphosphorylated PKCε V3 region peptide reveals that a consensus 14-3-3 site and a divergent 'gatekeeper' site cooperate to bind a single 14-3-3 dimer; thermodynamic data show markedly enhanced affinity for two-site versus single-site phosphopeptides, identifying Ser368 as a gatekeeper phosphorylation site essential for PKCε activation and cytokinesis completion. X-ray crystallography, isothermal titration calorimetry, PKCε kinase activity assay EMBO reports High 19662078
2009 14-3-3 epsilon interacts with Gli1/Gli2/Gli3 transcription factors in a PKA phosphorylation-dependent manner (identified by tandem affinity purification/mass spectrometry); a Gli2 mutant that cannot bind 14-3-3 showed 2–3× increased transcriptional activity; the phosphorylation sites responsible are distinct from proteolysis-related PKA sites, defining a novel PKA→14-3-3 binding mechanism that suppresses Hedgehog signaling independently of proteolysis. Tandem affinity purification (TAP)/mass spectrometry, co-immunoprecipitation, transcriptional reporter assay, phospho-site mutagenesis The Journal of biological chemistry Medium 19996099
2009 ASK2 interacts with 14-3-3 through phosphorylated S964; loss of this interaction (ASK2 S964A mutant) or ASK2 knockdown dramatically reduces ASK1 complexed with 14-3-3 and enhances ASK1 activation (T838 phosphorylation and JNK activation), establishing a dual engagement model whereby ASK2-14-3-3 binding controls signal relay to the ASK1 signalosome. Co-immunoprecipitation, phospho-site mutagenesis, ASK2 knockdown (RNAi), kinase activity assays (ASK1 T838 phosphorylation, JNK phosphorylation) Oncogene Medium 19935702
2009 14-3-3 tau (sigma and tau isoforms) can bind p53 phosphorylated at S366, S378, and T387; sigma and tau isoforms stabilize p53 protein levels in cells and bind p53 C-terminal phosphopeptides independently of specific phosphorylation sites (unlike epsilon and gamma which require phosphorylation), while epsilon and gamma stimulate p53 DNA-binding activity in vitro; all four isoforms transcriptionally activate wild-type p53, revealing isoform-specific mechanisms of p53 regulation. Co-immunoprecipitation in vivo, in vitro p53-DNA binding assay (EMSA), phosphopeptide binding, p53 transcriptional reporter, immunoblotting for p53 levels Nucleic acids research Medium 19933256
2013 14-3-3 interaction with LRRK2 (via LRRK2 kinase-dependent phosphorylation) is required for LRRK2 secretion in exosomes; disruption of the 14-3-3–LRRK2 interaction by a 14-3-3 inhibitor or acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, defining a function of the LRRK2–14-3-3 interaction in controlling LRRK2 extracellular release. Quantitative proteomics of urinary exosomes, co-immunoprecipitation, 14-3-3 inhibitor treatment, LRRK2 kinase inhibitor treatment, exosome purification and quantification Human molecular genetics Medium 23886663
2014 14-3-3 functions as a molecular adaptor to recruit chaperone-associated misfolded proteins to dynein motors for transport to aggresomes; the mechanism involves dimeric binding of 14-3-3 to both dynein-intermediate chain (DIC) and the Hsp70 co-chaperone BAG3, bridging these two complexes for retrograde transport of misfolded protein cargo. Co-immunoprecipitation, aggresome formation assay, dominant-negative and knockdown experiments Prion Medium 24549097
2018 PKA-dependent phosphorylation of SIK1, SIK2, and SIK3 (salt-inducible kinases) induces 14-3-3 binding and inhibits their catalytic activity; SIK1 and SIK3 each contain two functional PKA/14-3-3 sites, while SIK2 has four; loss of even a single 14-3-3 binding site abolishes 14-3-3 association and cAMP responsiveness in SIK1/3; multiple-site engagement dramatically increases binding affinity, demonstrating that 14-3-3 mediates cAMP-dependent inhibition of this kinase family. Co-immunoprecipitation, kinase activity assay, phospho-site mutagenesis, cAMP stimulation The FEBS journal High 29211348
2019 14-3-3 inhibits IRSp53 (I-BAR domain protein) by binding to two pairs of phosphorylation sites; crystallographic and quantitative binding data show each IRSp53 subunit independently binds one 14-3-3 dimer; FRET-sensor assay reveals opposite conformational changes in IRSp53 upon binding of activatory (Cdc42/Eps8) versus inhibitory (14-3-3) inputs; 14-3-3 binding inhibits IRSp53 membrane binding, defining a phosphorylation-dependent mechanism for suppression of filopodia formation. X-ray crystallography, bicistronic IRSp53 heterodimer expression, FRET conformational sensor, quantitative binding (ITC/SPR), in vitro membrane binding assay Nature communications High 30696821
2006 Phosphorylation of transglutaminase 2 (TG2) by PKA at Ser216 creates a 14-3-3 epsilon binding site; non-phosphorylated peptides or phosphorylation-site substituted peptides fail to pull down 14-3-3; 14-3-3 co-immunoprecipitates with TG2 after PKA activation in mouse embryonic fibroblasts (TG2+/+ but not TG2-/- cells), demonstrating PKA-dependent 14-3-3 recruitment to TG2 in vivo. Phosphopeptide pull-down, LC/MS identification, immunoblotting, co-immunoprecipitation after PKA activation Biochemical and biophysical research communications Medium 16870138

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell 3139 18439900
1996 Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 2236 8929531
2005 Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular cell 1538 15694340
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
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