Affinage

TJP2

Tight junction protein 2 · UniProt Q9UDY2

Length
1190 aa
Mass
134.0 kDa
Annotated
2026-04-28
93 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TJP2/ZO-2 is a MAGUK family scaffold protein that organizes epithelial tight junctions, suppresses proliferative gene expression in the nucleus, and enforces contact inhibition through the Hippo pathway. At tight junctions, ZO-2 binds claudins via its PDZ1 domain, occludin, ZO-1, cingulin, JAM-A, and F-actin, and together with ZO-1 is essential for claudin polymerization into TJ strands and paracellular barrier formation; its absence causes loss of barrier integrity, reduced apical membrane rigidity, and in the liver leads to progressive cholestatic disease (PFIC4) with diminished claudin-1 and BSEP expression (PMID:10601346, PMID:16923393, PMID:24614073, PMID:33465371). In the nucleus, ZO-2 represses AP-1- and β-catenin/TCF-dependent transcription by associating with Jun/Fos, c-Myc, and SAF-B, downregulates cyclin D1 via c-Myc/HDAC1 recruitment, and acts as a Hippo pathway scaffold that bridges LATS1 (via its SH3 domain) and YAP (via its PDZ domain) to promote YAP phosphorylation and cytoplasmic retention (PMID:14720506, PMID:17881732, PMID:39462647, PMID:12403786). ZO-2 subcellular distribution is controlled by multiple NLS/NES sequences regulated by PKC, c-Abl/JAK1 phosphorylation, SUMOylation at K730, K48-linked polyubiquitination at K759/K992 for proteasomal turnover, and calcium-dependent 14-3-3 association (PMID:16920099, PMID:31318316, PMID:36291162, PMID:27604867, PMID:41259016).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Identifying ZO-2 as a ZO-1-interacting MAGUK protein at tight junctions established the existence of a multi-protein scaffold at the cytoplasmic face of TJs beyond ZO-1 alone.

    Evidence Co-immunoprecipitation from MDCK cells with immunofluorescence localization

    PMID:8132716

    Open questions at the time
    • Binding domains not yet mapped
    • Functional role at TJ unknown
  2. 1996 High

    Determination of the full domain architecture (three PDZ, SH3, GuK domains) revealed the multi-interaction capacity of ZO-2 and explained how it could serve as a hub scaffold.

    Evidence cDNA cloning and sequence analysis with alternative splice isoform characterization

    PMID:8824195

    Open questions at the time
    • Ligands for each domain not identified
    • No functional assays for individual domains
  3. 1999 High

    Demonstration that ZO-2 directly binds claudins (via PDZ1), occludin, ZO-1, cingulin, and F-actin defined the molecular connections through which ZO-2 links transmembrane TJ proteins to the cytoskeleton.

    Evidence In vitro binding/cosedimentation assays, co-immunoprecipitation, and transfection of claudins into fibroblasts

    PMID:10575001 PMID:10601346 PMID:10613913

    Open questions at the time
    • Whether ZO-2 is sufficient for TJ strand formation unknown
    • Regulation of these interactions uncharacterized
  4. 2002 High

    Discovery that ZO-2 shuttles to the nucleus in subconfluent cells and interacts with SAF-B via PDZ1 revealed a non-redundant nuclear role distinct from ZO-1, linking TJ disassembly to changes in nuclear function.

    Evidence Immunofluorescence with leptomycin B and calcium switch; yeast two-hybrid and co-IP for SAF-B interaction

    PMID:11855865 PMID:12403786

    Open questions at the time
    • Transcriptional targets of nuclear ZO-2 unknown
    • NLS/NES sequences not yet mapped
  5. 2003 High

    A PDZ1 mutation causing familial hypercholanemia linked ZO-2 to human liver disease and showed that PDZ1 integrity is essential for hepatic TJ function.

    Evidence Patient genetic analysis with in vitro PDZ domain stability/binding assays and liver histology

    PMID:12704386

    Open questions at the time
    • Mechanism of cholestasis not resolved
    • Whether complete loss of function causes more severe disease unknown
  6. 2004 High

    Identification of ZO-2 as a transcriptional repressor of AP-1 targets through association with Jun/Fos/C/EBP, and mapping of multiple NLS/NES sequences, established how ZO-2 nuclear shuttling translates into gene regulation.

    Evidence GST pull-down, EMSA, reporter assays, NLS deletion analysis, nuclear export peptide assays

    PMID:14720506 PMID:15194440

    Open questions at the time
    • Genome-wide transcriptional targets not defined
    • Phosphorylation-dependent regulation of NES not yet shown
  7. 2006 High

    Double knockout/knockdown of ZO-1 and ZO-2 abolished TJ strand formation, proving these two proteins are the essential and sufficient scaffolds for claudin polymerization; four NES sequences with phosphorylation-dependent activation were mapped.

    Evidence Genetic epistasis (KO/KD/rescue in EpH4 cells); NES-ovalbumin injection assays with NES mutants

    PMID:16920099 PMID:16923393

    Open questions at the time
    • Relative contributions of ZO-1 vs ZO-2 not fully separated
    • In vivo confirmation of NES phosphoregulation lacking
  8. 2007 High

    ZO-2 was shown to repress cyclin D1 transcription through c-Myc/HDAC1 recruitment to the E-box, and ZO-2 knockdown increased paracellular permeability and disrupted fence function, connecting nuclear and junctional roles to cell cycle control and polarity.

    Evidence ChIP, reporter assays, co-IP for c-Myc; siRNA KD in MDCK with TEER, dextran permeability, and calcium switch

    PMID:17374535 PMID:17881732

    Open questions at the time
    • Whether cyclin D1 repression is the main growth-inhibitory mechanism unknown
    • Redundancy with ZO-1 at TJs not fully resolved
  9. 2008 High

    ZO-2 knockout embryos died at gastrulation with proliferation defects, apoptosis, and barrier failure, proving ZO-2 is essential for early mammalian development and non-redundant with ZO-1 in vivo.

    Evidence Gene knockout mice with embryo histology, permeability tracer, proliferation/apoptosis assays

    PMID:18172007

    Open questions at the time
    • Cell-type-specific requirements in later development unknown
    • Molecular basis of embryonic lethality not dissected
  10. 2010 High

    ZO-2 was found to interact with YAP2 via PDZ1 and facilitate its nuclear localization and pro-apoptotic activity, establishing ZO-2 as a Hippo pathway component; separately, TJP2 duplication causing overexpression was linked to progressive hearing loss (DFNA51).

    Evidence Co-IP, domain-deletion analysis, apoptosis assays (YAP2); family genomic analysis with phosphorylation readouts (DFNA51)

    PMID:20602916 PMID:20868367

    Open questions at the time
    • Whether ZO-2 scaffolds LATS-YAP phosphorylation not yet tested
    • DFNA51 mechanism remains correlative
  11. 2014 High

    Protein-truncating TJP2 mutations were shown to cause severe progressive familial intrahepatic cholestasis (PFIC4) with TJ ultrastructural disruption, establishing complete ZO-2 loss as a cause of Mendelian liver disease.

    Evidence Patient genetic analysis with immunolocalization and electron microscopy of hepatic TJs

    PMID:24614073

    Open questions at the time
    • Downstream molecular pathology (claudin, transporter levels) not fully characterized at this point
    • No animal model recapitulating PFIC4
  12. 2016 High

    SUMOylation at K730 was identified as a switch controlling ZO-2 subcellular localization and its ability to inhibit β-catenin/Wnt signaling; ZO-2 silencing was shown to cause cell hypertrophy via nuclear YAP/Akt/mTOR activation, integrating post-translational control with growth regulation.

    Evidence Ubc9-directed SUMOylation, site mutagenesis, reporter assays; siRNA KD with cell cycle/mTOR pathway analysis and in vivo uninephrectomy model

    PMID:27009203 PMID:27604867

    Open questions at the time
    • SUMO ligase identity unknown
    • Whether SUMOylation and ubiquitination are coordinated not tested
  13. 2019 High

    Ca2+-sensing receptor/PKC/WNK4 signaling was found to drive ZO-2 phosphorylation and TJ recruitment, while 14-3-3 proteins protect ZO-2 from degradation in low calcium, revealing how extracellular calcium signals control ZO-2 trafficking between cytoplasm and TJs.

    Evidence Co-IP, kinase inhibitors, calcium switch, domain mutagenesis including S261 in NLS

    PMID:31318316

    Open questions at the time
    • Direct WNK4 phosphorylation sites on ZO-2 not mapped
    • 14-3-3 binding stoichiometry and specificity not resolved
  14. 2021 High

    Liver-specific Tjp2 deletion in mice recapitulated key PFIC4 features including reduced claudin-1, BSEP/Abcb11, and canalicular defects, while nuclear ZO-2 was shown to co-import TEAD via PKCδ/ε-regulated shuttling, expanding ZO-2's nuclear transcriptional partnerships.

    Evidence Hepatocyte-specific conditional KO with EM, biochemistry, and dietary challenge; proximity ligation and kinase inhibitors for TEAD interaction

    PMID:33465371 PMID:34010016

    Open questions at the time
    • Whether TEAD nuclear import is the key driver of cholestasis phenotype untested
    • ZO-2-LATS scaffolding mechanism not yet reconstituted
  15. 2022 High

    K48-linked polyubiquitination at K759 and K992 was shown to target ZO-2 for proteasomal degradation, and interplay with K730 SUMOylation was demonstrated, establishing a post-translational code controlling ZO-2 turnover and TJ sealing; hepatocyte-specific Tjp2 loss was shown to derepress Yap/Taz and enable hepatocyte-to-cholangiocyte transdifferentiation.

    Evidence TUBES ubiquitin capture, site-directed mutagenesis, CHX chase, TEER; hepatocyte- vs cholangiocyte-specific KO with dietary DDC challenge

    PMID:36151109 PMID:36291162

    Open questions at the time
    • E3 ubiquitin ligase identity unknown
    • Full ubiquitin/SUMO crosstalk mechanism not resolved
  16. 2023 High

    ZO-2 was identified as essential for p190A RhoGAP-mediated LATS activation and as an ERK2-binding protein suppressing ERK phosphorylation, broadening ZO-2's scaffolding role to RhoGAP-Hippo and MAPK signaling.

    Evidence Co-IP, siRNA KD, LATS kinase activity assays, tumor growth assays (p190A); TMT proteomics, co-IP, orthotopic tumor models (ERK2)

    PMID:36966163 PMID:37995182

    Open questions at the time
    • Direct binding interface of p190A-ZO-2 not mapped
    • ERK2 interaction confirmed in single lab only
  17. 2024 High

    The scaffolding mechanism for Hippo signaling was reconstituted: ZO-2 bridges LATS1 via SH3 and YAP via PDZ domains to enable LATS1-dependent YAP phosphorylation; biophysically, ZO-2 loss reduces apical rigidity and increases TJ mechanical tension.

    Evidence Domain-deletion co-IP with LATS1 kinase/YAP phosphorylation assays; AFM and FRET tension probes in KD cells

    PMID:38473701 PMID:39462647

    Open questions at the time
    • Structural basis of SH3-LATS1 and PDZ-YAP interfaces not determined
    • How mechanical tension feedback integrates with Hippo signaling unknown
  18. 2025 High

    ZO-2 was localized to centrosomes and the basal body of primary cilia and shown to regulate mitotic spindle organization, and was independently identified as a stabilizer of the bile acid transporter NTCP at the cell surface required for HBV entry; c-Abl/JAK1 were identified as kinases that directly phosphorylate ZO-2 to control cell morphology and migration.

    Evidence Co-IP with spindle/centrosomal proteins and siRNA KD (cilia/spindle); LC-MS/MS immunopurification with KO functional HBV assay (NTCP); in vitro kinase assays with RNAi rescue (c-Abl/JAK1)

    PMID:40728639 PMID:41259016 PMID:41870046

    Open questions at the time
    • Centrosomal localization confirmed in single lab only
    • Whether NTCP stabilization contributes to PFIC4 pathology untested
    • JAK1 phosphorylation sites on ZO-2 not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase(s) targeting ZO-2, the structural basis for ZO-2's scaffolding of LATS1-YAP, the genome-wide transcriptional program controlled by nuclear ZO-2, and how ZO-2's centrosomal and ciliary functions relate to its established junctional and nuclear roles.
  • E3 ligase unknown
  • No high-resolution structure of ZO-2 scaffold complexes
  • No genome-wide ChIP-seq or nuclear transcriptomics for ZO-2
  • Centrosome/cilia role not independently replicated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0140110 transcription regulator activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 6 GO:0005886 plasma membrane 5 GO:0005856 cytoskeleton 4 GO:0005829 cytosol 3 GO:0005815 microtubule organizing center 1 GO:0005929 cilium 1
Pathway
R-HSA-1500931 Cell-Cell communication 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 2
Partners
ABL1CGNCLDN1F11RLATS1OCLNTJP1YAP1
Complex memberships
Tight junction plaque complexZO-1/ZO-2 heterodimer

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 TJP2/ZO-2 was identified as a tight junction-associated peripheral membrane protein that co-immunoprecipitates with ZO-1 from MDCK cell extracts, establishing it as a member of the MAGUK protein family containing guanylate kinase-like and other conserved domains, localized exclusively to epithelial tight junctions (not fascia adherens). Co-immunoprecipitation, immunofluorescence, cDNA cloning and sequence analysis The Journal of cell biology High 8132716
1996 ZO-2 contains three PDZ domains, an SH3 domain, and a guanylate kinase-like domain, and undergoes alternative splicing producing isoforms differing in a 36-amino acid C-terminal region; the domain architecture indicates multiple protein-protein interaction capacities. cDNA cloning, sequence analysis of multiple ZO-2 cDNA clones The Journal of biological chemistry High 8824195
1999 ZO-2 directly binds to the COOH-terminal YV sequence of claudins-1 through -8 via its PDZ1 domain in vitro; ZO-2 is recruited to claudin-based networks through both PDZ1/claudin-COOH and PDZ2/ZO-1-PDZ2 interactions. In vitro binding assays, transfection of claudins into L fibroblasts, co-localization in epithelial cells The Journal of cell biology High 10601346
1999 ZO-2 directly interacts with F-actin in vitro (cosedimentation assay) and directly binds both ZO-1 and occludin; in vivo, ZO-1 and ZO-2 exist primarily as independent ZO-1·ZO-2 complexes rather than a trimeric ZO-1·ZO-2·ZO-3 complex. Actin cosedimentation, in vitro binding assays with recombinant proteins, immunoprecipitation The Journal of biological chemistry High 10575001
1999 Cingulin interacts with ZO-2 via an NH2-terminal fragment (residues 1-378) in pull-down assays from epithelial and insect cell lysates; ZO-1 and ZO-2 immunoprecipitates contain cingulin, confirming in vivo interaction. Pull-down assays, co-immunoprecipitation The Journal of cell biology High 10613913
2000 Protein 4.1R isoforms (135 and 150 kDa) specifically interact with ZO-2; the interaction domains were mapped to exons 19-21 of 4.1R and residues 1054-1118 of ZO-2, providing a molecular link between tight junctions and the actin/spectrin cytoskeleton. Yeast two-hybrid, immunocolocalization, immunoprecipitation, in vitro binding studies The Journal of biological chemistry High 10874042
2001 Adenovirus type 9 E4-ORF1 oncoprotein binds ZO-2 via a C-terminal PDZ-binding motif interacting with the first PDZ domain of ZO-2; this interaction causes aberrant cytoplasmic sequestration of ZO-2. Overexpression of wild-type ZO-2 (but not a mutant lacking PDZ2/3) interfered with E4-ORF1-induced focus formation, implicating ZO-2 as a candidate tumor suppressor. Co-immunoprecipitation, immunofluorescence, focus formation assays, domain-deletion mutants The EMBO journal High 11598001
2002 ZO-2 localizes to the nucleus of sparse epithelial cells in clusters that partially co-localize with splicing factor SC35; nuclear staining diminishes at confluence and can be induced by impairing cell-cell contacts or mechanical injury. ZO-2 nuclear translocation is mediated by the actin cytoskeleton and involves shuttling of a pre-existing pool rather than newly synthesized protein. Nuclear export is sensitive to leptomycin B. Immunofluorescence, live-cell imaging, leptomycin B treatment, calcium switch assay Experimental cell research High 11855865
2002 Nuclear ZO-2 directly interacts with the DNA-binding protein scaffold attachment factor-B (SAF-B) via its PDZ-1 domain; this association was confirmed by yeast two-hybrid, co-immunoprecipitation, and co-localization in nuclei of epithelial and endothelial cells. ZO-1 does not associate with SAF-B, indicating non-redundant nuclear functions. Yeast two-hybrid, co-immunoprecipitation, co-localization by confocal microscopy The Journal of biological chemistry High 12403786
2003 A TJP2 mutation in the first PDZ domain (found in Amish families with familial hypercholanemia) reduces PDZ domain stability and ligand binding in vitro, and is associated with morphological changes in hepatic tight junctions. In vitro PDZ domain stability/binding assays, patient genetic analysis, liver histology Nature genetics High 12704386
2003 Tyrosine phosphorylation of the C-terminal tail of occludin (by c-Src in vitro) significantly reduces binding of ZO-2 (as well as ZO-1 and ZO-3) to occludin, but does not affect occludin-F-actin binding. In vitro phosphorylation (c-Src), GST pull-down binding assays Biochemical and biophysical research communications High 12604349
2004 ZO-2 associates with Jun, Fos and C/EBP transcription factors both at the nucleus and at the TJ region of epithelial cells; this association downregulates AP-1-dependent gene transcription in a dose-dependent manner, with both amino and carboxyl domains of ZO-2 capable of inhibiting transcription. GST pull-down, gel shift analysis (EMSA), co-immunoprecipitation, reporter gene (CAT) assays, immunolocalization Experimental cell research High 14720506
2004 Nuclear ZO-2 is present in the nuclear matrix and co-immunoprecipitates with lamin B1 and actin. Multiple NLS signals in the amino region mediate nuclear import; only the second of two putative NES sequences is functional (confirmed by ovalbumin-coupled peptide nuclear injection assay). The NLS region also regulates AP-1-dependent transcription. Nuclear fractionation, co-immunoprecipitation, NLS deletion analysis, nuclear export assay with ovalbumin-coupled peptides Experimental cell research High 15194440
2004 ARVCF interacts with ZO-2 (and ZO-1) via a C-terminal PDZ-binding motif; the PDZ domains of ZO-2 can mediate nuclear localization of ARVCF, establishing a PDZ-domain-dependent mechanism for nuclear targeting. Co-immunoprecipitation, localization experiments, domain deletion analysis Molecular biology of the cell Medium 15456900
2005 hScrib directly interacts with ZO-2 via two PDZ domains of hScrib and the C-terminal PDZ-binding motif of ZO-2; a point mutation in the LRR of hScrib that delocalizes it from the plasma membrane also abolishes ZO-2 interaction. Direct interaction assay, co-localization, mutagenesis FEBS letters Medium 15975580
2006 ZO-2 (along with ZO-1) is required for tight junction strand formation and claudin polymerization; double knockdown/knockout of ZO-1 and ZO-2 in epithelial cells abolishes TJ formation. ZO-1 and ZO-2 independently determine the site of claudin polymerization, requiring dimerization and recruitment to the lateral membrane. Homologous recombination knockout + siRNA knockdown, exogenous ZO-1/ZO-2 rescue, forced membrane dimerization Cell High 16923393
2006 ZO-2 has four functional nuclear export signals (NES-0, NES-1, NES-2, NES-3); NES-0 and NES-3 are directly functional (confirmed by nuclear injection assay with ovalbumin-coupled peptides); NES-1 becomes functional upon phosphorylation at Ser369; mutation of any single NES is sufficient to cause nuclear accumulation of full-length ZO-2. Nuclear export assay with microinjection of NES-ovalbumin conjugates, leptomycin B sensitivity, transfection of NES mutants Experimental cell research High 16920099
2006 EcN (probiotic E. coli Nissle 1917) restores epithelial barrier integrity in EPEC-infected cells by enhancing ZO-2 expression and redistributing ZO-2 to cell boundaries, a process mediated by silencing of PKCζ. DNA microarray, immunofluorescence, Western blotting, PKC inhibitors, TEER measurement Cellular microbiology Medium 17087734
2007 ZO-2 downregulates cyclin D1 transcription via an E box in the cyclin D1 promoter by interacting with c-Myc; the complex also recruits HDAC1 to the E box, and HDAC activity is required for ZO-2-mediated repression. ZO-2 and c-Myc co-immunoprecipitate. Reporter gene (CAT) assays, deletion analysis, EMSA, ChIP, co-immunoprecipitation Molecular biology of the cell High 17881732
2007 ZO-2 silencing in MDCK cells increases paracellular permeability (gate function), disrupts fence function (non-polarized E-cadherin distribution), decreases occludin and E-cadherin expression in mature monolayers, delays arrival of ZO-1 and occludin to the plasma membrane during calcium switch, and causes atypical monolayer architecture with widened intercellular spaces. siRNA knockdown, TEER measurement, dextran permeability assay, immunofluorescence, calcium switch assay Experimental cell research High 17374535
2008 ZO-2 knockout mice die shortly after implantation due to arrest in early gastrulation; ZO-2-deficient embryos show decreased proliferation at E6.5, increased apoptosis at E7.5, altered apical junctional complex architecture, and increased paracellular permeability. ZO-3 knockout mice have no obvious phenotype. Gene knockout, embryo histology, permeability tracer assay, immunostaining, cell proliferation/apoptosis assays Molecular and cellular biology High 18172007
2008 ZO-1 and ZO-2 are required for integration of myosin-2 into the zonula adherens (ZA); in ZO1(ko)/2(kd) cells, myosin-2 fails to integrate into ZA, and rescue by full-length ZO-1 or ZO-2 (or ZO-1 lacking PDZ1/2 but not PDZ1/2/3) restores myosin-2 integration. ZO-1/2-dependent RhoA/ROCK signaling spatiotemporally regulates ZA establishment. Knockout/knockdown, domain-deletion rescue, FRET RhoA activity assay, immunofluorescence Molecular biology of the cell High 18596233
2010 ZO-2 forms a complex with YAP2 via the first PDZ domain of ZO-2 binding the PDZ-binding motif of YAP2; endogenous ZO-2 and YAP2 co-localize in the nucleus. ZO-2 facilitates nuclear localization and pro-apoptotic function of YAP2 in a PDZ-domain-dependent manner. Co-immunoprecipitation, co-localization, domain-deletion analysis, apoptosis assays The Biochemical journal High 20868367
2010 Genomic duplication of TJP2 leads to overexpression of ZO-2 protein; this overexpression decreases phosphorylation of GSK-3β and alters expression of apoptosis-regulating genes, causing progressive hearing loss (DFNA51) via increased susceptibility to apoptosis of inner ear cells. Genomic sequencing, family analysis, RT-PCR, Western blot, phosphorylation assays American journal of human genetics Medium 20602916
2013 JAM-A associates directly with ZO-2 (and indirectly with afadin); this complex, along with PDZ-GEF1, activates the small GTPase Rap2c to regulate epithelial barrier function and apical cytoskeleton contraction via RhoA and nonmuscle myosin phosphorylation. Direct binding assay, co-immunoprecipitation, siRNA knockdown, permeability assay, RhoA activity assay Molecular biology of the cell High 23885123
2013 SNX27 interacts with ZO-2 via the PDZ domain of SNX27 and the C-terminal PDZ-binding motif of ZO-2; when tight junctions are disrupted by calcium chelation, ZO-2 transiently localizes to SNX27-positive early endosomes. Depletion of SNX27 decreases ZO-2 (but not ZO-1) mobility at junctions and increases junctional permeability. Proteomics, co-immunoprecipitation, co-localization, FRAP, permeability assay, siRNA knockdown The Biochemical journal High 23826934
2014 Protein-truncating mutations in TJP2 cause failure of ZO-2 protein localization and disruption of tight junction structure, leading to severe cholestatic liver disease (PFIC4). Patient genetic analysis, protein localization studies in patient tissue, electron microscopy of tight junctions Nature genetics High 24614073
2016 ZO-2 is SUMOylated; it associates with SUMO E2 enzyme Ubc9 and deconjugating proteases SENP1/SENP3; lysine 730 in the GuK domain is a SUMOylation site. Mutation of K730 (mimicking constitutive SUMOylation) retains ZO-2 in cytoplasm and abolishes its inhibitory effect on GSK3β activity and β-catenin/TCF-4-mediated transcription; ZO-2 directly binds GSK3β and forms a complex with β-catenin. Co-immunoprecipitation, Ubc9 fusion-directed SUMOylation, site-directed mutagenesis, reporter gene assays Cellular and molecular life sciences High 27604867
2016 ZO-2 silencing in renal epithelial MDCK cells induces cell hypertrophy by: (1) prolonging G1 phase via increased cyclin D1; (2) increasing protein synthesis via nuclear accumulation of YAP leading to reduced PTEN expression, activation of Akt/mTOR/S6K1. In vivo, compensatory renal hypertrophy after uninephrectomy is accompanied by decreased ZO-2 and nuclear YAP. siRNA knockdown, cell cycle analysis, flow cytometry, reporter assays, mTOR pathway inhibitors, in vivo uninephrectomy model Molecular biology of the cell High 27009203
2018 The organophosphate pesticide methamidophos covalently binds to ZO-2 at serine, tyrosine, and lysine residues (identified by mass spectrometry), inducing ZO-2 phosphorylation and reducing ZO-2/occludin interaction. Covalent modification at a lysine ubiquitination site (K) interferes with ZO-2 degradation and TJ sealing, demonstrated by transfection with a ZO-2 mutant at a MET target lysine residue. Mass spectrometry, co-immunoprecipitation, site-directed mutagenesis, transfection, permeability assay Toxicology and applied pharmacology Medium 30291936
2019 Activation of the Ca2+-sensing receptor triggers PKC/WNK4 signaling, leading to ZO-2 phosphorylation and concentration at tight junctions. In low calcium, ZO-2 is protected from degradation by association with 14-3-3ζ and 14-3-3σ proteins; upon Ca2+ restoration, ZO-2/14-3-3 complexes move to cell borders and dissociate (14-3-3 is proteasomally degraded; ZO-2 integrates into TJs). The unique region 2 of ZO-2 and S261 within an NLS are critical for 14-3-3 interaction and nuclear import. Co-immunoprecipitation, kinase inhibitors, calcium switch assay, domain mutagenesis, immunofluorescence Molecular biology of the cell High 31318316
2021 Liver-specific deletion of Tjp2 in mice causes lower Cldn1 protein levels, dilated canaliculi, reduced microvilli density, aberrant radixin and BSEP distribution, mild progressive cholestasis, and lower expression of bile acid transporter Abcb11/Bsep and detoxification enzyme Cyp2b10; a cholic acid diet causes severe cholestasis and liver necrosis in Tjp2-deficient but not control mice. Conditional knockout in hepatocytes/cholangiocytes, biochemical analyses, electron microscopy, immunostaining, fluorescein-dextran permeability Gastroenterology High 33465371
2021 Nuclear ZO-2 facilitates TEAD entry into the nucleus; ZO-2 and TEAD interact in the cytoplasm (confirmed by proximity ligation, immunoprecipitation, pull-down); inhibition of nPKCδ promotes ZO-2/TEAD cytoplasmic interaction and co-importation. Nuclear exit of ZO-2/TEAD is enhanced by nPKCε-mediated activation of a ZO-2 NES. Proximity ligation assay, co-immunoprecipitation, GST pull-down, siRNA knockdown, kinase inhibitors, immunofluorescence Molecular biology of the cell High 34010016
2021 ZO-2 functions as a scaffold for the Hippo pathway by associating with LATS1; ZO-2 silencing reduces LATS kinase activity and leads to nuclear accumulation of YAP. In liver steatosis, ZO-2 is silenced and this correlates with diminished LATS activity; metformin (AMPK activator blocking JNK) restores ZO-2 and claudin-1 expression in steatotic liver. Co-immunoprecipitation (ZO-2/LATS1), siRNA knockdown, kinase activity assays, in vivo obese rat model, immunofluorescence Tissue barriers Medium 34689705
2022 ZO-2 is polyubiquitinated at K759 and K992 (K48-linked, targeting for proteasomal degradation), confirmed by mutation of these sites reducing ubiquitination and extending ZO-2 half-life. K730 (SUMOylation site) mutation increases ubiquitination and decreases half-life. Mutation of any of these lysines reduces TJ sealing. Co-immunoprecipitation with ubiquitin, TUBES (tandem ubiquitin-binding entities), site-directed mutagenesis, half-life assay (CHX chase), TEER measurement Cells High 36291162
2022 In the mouse liver, Tjp2 negatively regulates Yap and Wwtr1/Taz protein expression; hepatocyte-specific (but not cholangiocyte-specific) Tjp2 deletion leads to DDC-diet-induced hepatocyte-to-cholangiocyte transdifferentiation in a Yap/Taz-dependent manner. Conditional knockout (hepatocyte- vs cholangiocyte-specific), immunostaining, Yap/Taz protein level analysis, dietary challenge NPJ Regenerative medicine High 36151109
2023 ZNF582 upregulates TJP2 protein expression; increased TJP2 then binds ERK2, promotes ERK2 protein expression, and suppresses ERK2 phosphorylation, thereby inhibiting ccRCC growth and metastasis. TMT quantitative proteomics, co-immunoprecipitation, Western blot, orthotopic tumor models Cell death & disease Medium 36966163
2023 ZO-2 is required for p190A RhoGAP to activate LATS kinases and the Hippo pathway; interaction of p190A with ZO-2 is dependent on RasGAP. Both RasGAP and ZO-2 are necessary for p190A to promote mesenchymal-to-epithelial transition and contact inhibition of proliferation. Co-immunoprecipitation, siRNA knockdown, LATS kinase activity assays, tumor growth assays, reporter assays Cell reports High 37995182
2024 ZO-2 acts as a scaffold to promote LATS1/YAP interaction: ZO-2 brings LATS1 (via SH3 domain) and YAP (via PDZ domain) together, enabling LATS1-dependent phosphorylation and cytoplasmic retention/inactivation of YAP, maintaining Hippo pathway activation and contact inhibition of proliferation. Co-immunoprecipitation, domain-deletion analysis, LATS1 kinase assays, YAP phosphorylation assays The FEBS journal High 39462647
2024 Absence of ZO-2 reduces apical membrane rigidity, inhibits γ-actin and JAM-A recruitment to cell borders, facilitates p114RhoGEF and afadin accumulation at junctions, and increases mechanical tension at TJs (measured by FRET). ZO-2 KD cells show impaired responses to substrate stiffness and topography, with increased YAP and Snail nuclear accumulation. Atomic force microscopy, FRET tension probes, immunofluorescence, siRNA knockdown, in silico binding stability analysis International journal of molecular sciences High 38473701
2025 ZO-2 colocalizes with CEP164 at the distal appendage of the mother centriole and is present at mitotic spindle poles, the basal body of primary cilia, and spermatozoa tails. ZO-2 depletion alters centriolar protein levels (CEP164, centriolin, CEP135), inhibits astral and mitotic spindle microtubule growth, increases NuMA and decreases KIF14/TPX2/p-Aurora at spindle poles, reduces mitotic spindle length, and blocks primary cilia development. KIF14, NuMA, and p-Aurora co-immunoprecipitate with ZO-2; NuMA and Aurora-A bind distinct ZO-2 segments. Immunofluorescence, co-immunoprecipitation, siRNA knockdown, domain binding assays Cell and tissue research Medium 40728639
2025 ZO-2 is identified as a novel NTCP-binding protein by immunopurification/LC-MS/MS; ZO-2 knockdown or knockout reduces NTCP at the cell surface, decreasing HBV attachment and infection. HBV surface element preS1 dissociates NTCP from ZO-2 and promotes formation of NTCP-preS1-actin complexes that are internalized; actin polymerization is required for preS1 internalization and HBV infection. Immunopurification + LC-MS/MS, siRNA knockdown/knockout, HBV infection assay, co-immunoprecipitation, actin inhibitor (latrunculin A) mBio High 41870046
2025 c-Abl directly binds to and phosphorylates the C-terminus of ZO-2; c-Abl also stimulates JAK1 activity, which subsequently phosphorylates the N-terminus of ZO-2. By RNAi knockdown/rescue, c-Abl regulates cellular morphology and migration through ZO-2 phosphorylation. In vitro kinase assay, co-immunoprecipitation, RNAi knockdown/rescue, traction force microscopy FASEB journal High 41259016

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. The Journal of cell biology 919 10601346
2006 ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 656 16923393
1994 Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. The Journal of cell biology 396 8132716
1999 Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. The Journal of biological chemistry 384 10575001
2006 Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCzeta redistribution resulting in tight junction and epithelial barrier repair. Cellular microbiology 309 17087734
1993 Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin and ZO-2. The Journal of cell biology 230 8421059
1999 Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. The Journal of cell biology 229 10613913
2003 Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nature genetics 213 12704386
2014 Mutations in TJP2 cause progressive cholestatic liver disease. Nature genetics 204 24614073
2010 Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. The Biochemical journal 172 20868367
2003 Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochemical and biophysical research communications 156 12604349
2008 Early embryonic lethality of mice lacking ZO-2, but Not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. Molecular and cellular biology 153 18172007
2002 Nuclear localization of the tight junction protein ZO-2 in epithelial cells. Experimental cell research 151 11855865
2004 The tight junction protein ZO-2 associates with Jun, Fos and C/EBP transcription factors in epithelial cells. Experimental cell research 134 14720506
2002 The tight junction protein ZO-2 localizes to the nucleus and interacts with the heterogeneous nuclear ribonucleoprotein scaffold attachment factor-B. The Journal of biological chemistry 131 12403786
2000 Characterization of the interaction between protein 4.1R and ZO-2. A possible link between the tight junction and the actin cytoskeleton. The Journal of biological chemistry 124 10874042
2000 Tight junction proteins ZO-1, ZO-2, and occludin along isolated renal tubules. Kidney international 111 10844608
2017 An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Scientific reports 107 28924228
1998 Subcellular distribution of tight junction-associated proteins (occludin, ZO-1, ZO-2) in rodent skin. The Journal of investigative dermatology 107 9620290
2013 JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function. Molecular biology of the cell 102 23885123
1996 The tight junction protein ZO-2 contains three PDZ (PSD-95/Discs-Large/ZO-1) domains and an alternatively spliced region. The Journal of biological chemistry 90 8824195
2009 Roles of ZO-1 and ZO-2 in establishment of the belt-like adherens and tight junctions with paracellular permselective barrier function. Annals of the New York Academy of Sciences 87 19538286
2010 Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51. American journal of human genetics 82 20602916
2004 Association of ARVCF with zonula occludens (ZO)-1 and ZO-2: binding to PDZ-domain proteins and cell-cell adhesion regulate plasma membrane and nuclear localization of ARVCF. Molecular biology of the cell 80 15456900
2007 Cyclin D1 is transcriptionally down-regulated by ZO-2 via an E box and the transcription factor c-Myc. Molecular biology of the cell 79 17881732
2007 ZO-2 silencing in epithelial cells perturbs the gate and fence function of tight junctions and leads to an atypical monolayer architecture. Experimental cell research 78 17374535
2001 Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2. The EMBO journal 76 11598001
2004 Characterization of the tight junction protein ZO-2 localized at the nucleus of epithelial cells. Experimental cell research 71 15194440
2009 Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. International journal of molecular medicine 67 19148554
2006 Altered expression of ZO-1 and ZO-2 in Sertoli cells and loss of blood-testis barrier integrity in testicular carcinoma in situ. Neoplasia (New York, N.Y.) 66 17217619
2010 Assessments of tight junction proteins occludin, claudin 5 and scaffold proteins ZO1 and ZO2 in endothelial cells of the rat blood-brain barrier: cellular responses to neurotoxicants malathion and lead acetate. Neurotoxicology 63 20970449
2000 Organization and expression of the human zo-2 gene (tjp-2) in normal and neoplastic tissues. Biochimica et biophysica acta 63 11018256
2005 hScrib interacts with ZO-2 at the cell-cell junctions of epithelial cells. FEBS letters 62 15975580
2008 ZO-1- and ZO-2-dependent integration of myosin-2 to epithelial zonula adherens. Molecular biology of the cell 60 18596233
2015 Mutations in TJP2, encoding zona occludens 2, and liver disease. Tissue barriers 50 26451340
2017 Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing. Journal of gastroenterology 48 29238877
2008 Heterocellular interaction enhances recruitment of alpha and beta-catenins and ZO-2 into functional gap-junction complexes and induces gap junction-dependant differentiation of mammary epithelial cells. Experimental cell research 48 18775424
1999 Tight junction protein ZO-2 is differentially expressed in normal pancreatic ducts compared to human pancreatic adenocarcinoma. International journal of cancer 48 10360833
2016 ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway. Molecular biology of the cell 47 27009203
2007 Identification, tissue distribution and developmental expression of tjp1/zo-1, tjp2/zo-2 and tjp3/zo-3 in the zebrafish, Danio rerio. Gene expression patterns : GEP 39 17632043
2008 Tight junction protein ZO-2 expression and relative function of ZO-1 and ZO-2 during mouse blastocyst formation. Experimental cell research 36 18817772
2006 The tight junction protein ZO-2 has several functional nuclear export signals. Experimental cell research 35 16920099
2021 Protective Functions of ZO-2/Tjp2 Expressed in Hepatocytes and Cholangiocytes Against Liver Injury and Cholestasis. Gastroenterology 30 33465371
2012 ZO-2, a tight junction scaffold protein involved in the regulation of cell proliferation and apoptosis. Annals of the New York Academy of Sciences 27 22671599
2008 Bile duct ligation in the rat causes upregulation of ZO-2 and decreased colocalization of claudins with ZO-1 and occludin. Histochemistry and cell biology 26 18197414
2014 ZO-1 and ZO-2 are required for extra-embryonic endoderm integrity, primitive ectoderm survival and normal cavitation in embryoid bodies derived from mouse embryonic stem cells. PloS one 25 24905925
2019 TJP2 hepatobiliary disorders: Novel variants and clinical diversity. Human mutation 24 31696999
2018 Effects of the differential expression of ZO-1 and ZO-2 on podocyte structure and function. Genes to cells : devoted to molecular & cellular mechanisms 24 29845705
2013 Sorting nexin 27 (SNX27) associates with zonula occludens-2 (ZO-2) and modulates the epithelial tight junction. The Biochemical journal 24 23826934
1999 zo-2 gene alternative promoters in normal and neoplastic human pancreatic duct cells. International journal of cancer 22 10495427
2018 The organophosphate pesticide methamidophos opens the blood-testis barrier and covalently binds to ZO-2 in mice. Toxicology and applied pharmacology 21 30291936
2009 The tight junction protein ZO-2 blocks cell cycle progression and inhibits cyclin D1 expression. Annals of the New York Academy of Sciences 21 19538296
2015 Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment. Chinese medical journal 20 26668150
2019 Novel compound heterozygote mutations of TJP2 in a Chinese child with progressive cholestatic liver disease. BMC medical genetics 19 30658709
2013 Papillomavirus E6 oncoprotein up-regulates occludin and ZO-2 expression in ovariectomized mice epidermis. Experimental cell research 19 23948304
2016 SUMOylation regulates the intracellular fate of ZO-2. Cellular and molecular life sciences : CMLS 17 27604867
2014 Different effects of ZO-1, ZO-2 and ZO-3 silencing on kidney collecting duct principal cell proliferation and adhesion. Cell cycle (Georgetown, Tex.) 17 25486565
2019 Activation of the Ca2+ sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3. Molecular biology of the cell 16 31318316
2013 Beyond cell-cell adhesion: Emerging roles of the tight junction scaffold ZO-2. Tissue barriers 14 24665396
2009 The tight junction protein ZO-2 mediates proliferation of vascular smooth muscle cells via regulation of Stat1. Cardiovascular research 14 19380416
2023 Treatment with an ileal bile acid transporter inhibitor in patients with TJP2 deficiency. Clinics and research in hepatology and gastroenterology 13 37499899
2017 PARP‑1 may be involved in hydroquinone‑induced apoptosis by poly ADP‑ribosylation of ZO‑2. Molecular medicine reports 13 28983606
1998 Protein-binding domains of the tight junction protein, ZO-2, are highly conserved between avian and mammalian species. Biochemical and biophysical research communications 13 9837755
2023 ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation. Cell death & disease 12 36966163
2002 [LIM protein KyoT2 interacts with human tight junction protein ZO-2-i3]. Yi chuan xue bao = Acta genetica Sinica 12 12645256
2023 GNAQ-Regulated ZO-1 and ZO-2 Act as Tumor Suppressors by Modulating EMT Potential and Tumor-Repressive Microenvironment in Lung Cancer. International journal of molecular sciences 11 37240145
2021 ZO-2 favors Hippo signaling, and its re-expression in the steatotic liver by AMPK restores junctional sealing. Tissue barriers 11 34689705
2013 Alu-related transcript of TJP2 gene as a marker for colorectal cancer. Gene 11 23612256
2022 ZO-2/Tjp2 suppresses Yap and Wwtr1/Taz-mediated hepatocyte to cholangiocyte transdifferentiation in the mouse liver. NPJ Regenerative medicine 10 36151109
2021 Tight junction protein ZO-2 modulates the nuclear accumulation of transcription factor TEAD. Molecular biology of the cell 10 34010016
2011 The tight junction protein ZO-2 and Janus kinase 1 mediate intercellular communications in vascular smooth muscle cells. Biochemical and biophysical research communications 10 21679692
2021 Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients. Frontiers in cell and developmental biology 9 34504838
2015 Chronic hypoxia down-regulates tight junction protein ZO-2 expression in children with cyanotic congenital heart defect. ESC heart failure 9 27398226
2003 Dynamic assembly of tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin during mouse tooth development. Histology and histopathology 9 12507281
2024 The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography. International journal of molecular sciences 8 38473701
2019 ZO-2 Suppresses Cell Migration Mediated by a Reduction in Matrix Metalloproteinase 2 in Claudin-18-Expressing Lung Adenocarcinoma A549 Cells. Biological & pharmaceutical bulletin 8 30713254
2024 Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis. Hepatology (Baltimore, Md.) 6 38447037
2022 Polyubiquitination and SUMOylation Sites Regulate the Stability of ZO-2 Protein and the Sealing of Tight Junctions. Cells 4 36291162
2023 Silenced LASP1 interacts with DNMT1 to promote TJP2 expression and attenuate articular cartilage injury in mice by suppressing TJP2 methylation. The Kaohsiung journal of medical sciences 3 37578083
2023 p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP. Cell reports 3 37995182
2023 Transcriptomic Analysis of Tight Junction Proteins Demonstrates the Aberrant Expression and Function of Zona Occludens 2 (ZO-2) Protein in Stanford Type A Aortic Dissection. Journal of personalized medicine 3 38138924
2024 A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway. The FEBS journal 2 39462647
2023 p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor suppressor function mediated by p190A RhoGAP. bioRxiv : the preprint server for biology 2 37292741
2016 [Progressive familial intrahepatic cholestasis related to mutation of the TJP2 gene: recent advances]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 2 26983395
2025 Rotenone inhibited osteosarcoma metastasis by modulating ZO-2 expression and location via the ROS/Ca2+/AMPK pathway. Redox report : communications in free radical research 1 40247635
2024 Molecular alterations associated with pathophysiology in liver-specific ZO-1 and ZO-2 knockout mice. Cell structure and function 1 39322562
2021 Case Report: A Novel Single Variant TJP2 Mutation in a Case of Benign Recurrent Intrahepatic Cholestasis. JPGN reports 1 37205944
2026 ZO-2 determines cell membrane localization of receptor NTCP and supports hepatitis B virus infection. mBio 0 41870046
2025 Contact and communication: ZO-2 and the Hippo pathway. The FEBS journal 0 39910408
2025 Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level. Journal of human genetics 0 40251428
2025 ZO-2 is a scaffold at the centriole and mitotic spindle poles that enhances microtubule stability and supports the proper development of mitotic spindles and cilia. Cell and tissue research 0 40728639
2025 ZO-1/Tjp1 and ZO-2/Tjp2 deletion in retinal pigment epithelium causes progressive retinal degeneration. iScience 0 41210963
2025 c-Abl Kinase Targets Tight Junction Protein ZO-2 in Regulation of Cell Migration and Morphology. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41259016