Affinage

WWP1

NEDD4-like E3 ubiquitin-protein ligase WWP1 · UniProt Q9H0M0

Length
922 aa
Mass
105.2 kDa
Annotated
2026-06-11
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WWP1 is a multidomain HECT-family E3 ubiquitin ligase that controls the abundance, localization, and activity of a broad set of substrates across development, growth signaling, metabolism, and immunity (PMID:10903445, PMID:15221015). Its architecture couples an N-terminal C2 domain and four WW domains for substrate recognition and membrane targeting to a C-terminal catalytic HECT domain whose two-lobed fold depends on conformational flexibility at an interlobe hinge for ubiquitin transfer (PMID:12535537, PMID:10903445). Substrate selection is achieved largely through WW domain engagement of PY/PPxY motifs, and catalysis is held in check by intramolecular C2/WW–HECT autoinhibitory contacts that bias the enzyme toward monoubiquitination; binding of cofactors such as Smad7 relieves this autoinhibition to switch WWP1 to processive polyubiquitination, and cancer-associated mutations achieve the same de-repression constitutively (PMID:26152726, PMID:29635000). WWP1 deposits multiple ubiquitin linkage types with distinct outcomes: K48-linked chains drive proteasomal degradation of TβRI, KLF5, KLF15, TRAF6, TXNIP, HIPK3, p27Kip1, and NLRP3 (PMID:15221015, PMID:16223724, PMID:21795702, PMID:23799152, PMID:30830866, PMID:39364720, PMID:40280416, PMID:35508474), whereas non-degradative K63-linked chains stabilize or functionally activate ΔNp63, mutant huntingtin, and JARID1B (PMID:20951678, PMID:27107943, PMID:40627385), K27-linked chains stabilize DVL2 (PMID:34139860), and monoubiquitination of AMOTL2 licenses LATS2-dependent Hippo signaling (PMID:34404733). A central oncogenic axis is its suppression of the PTEN tumor suppressor by polyubiquitination that blocks PTEN dimerization and membrane recruitment; this activity is transcriptionally driven by MYC and is amenable to pharmacologic inhibition by indole-3-carbinol (PMID:31097636, PMID:34907909). Germline gain-of-function WWP1 variants that hyperactivate the enzyme cause excessive PTEN inactivation and constitutive PI3K signaling in patients (PMID:32459922). Through K48-linked degradation of JunB upstream of Runx2, WWP1 also restrains osteoblast differentiation (PMID:21809421, PMID:23553732), and it acts at primary cilia to limit ciliary Smo via Ptch1 (PMID:34161574), at cell junctions through Crumbs polarity proteins (PMID:34404733), and at the Golgi via its C2 domain (PMID:39578509).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    Establishing the domain architecture and an essential organismal role framed WWP1 as a conserved C2-WW-HECT ligase rather than an uncharacterized ORF.

    Evidence Cloning/domain analysis of murine Wwp1 and RNAi of the C. elegans ortholog

    PMID:10903445

    Open questions at the time
    • Did not identify substrates
    • Embryonic lethality phenotype not connected to a molecular pathway
  2. 2003 High

    Solving the HECT domain structure answered how WWP1 catalyzes ubiquitin transfer, showing that interlobe hinge flexibility is mechanistically required.

    Evidence X-ray crystallography of the HECT domain plus active-site mutagenesis

    PMID:12535537

    Open questions at the time
    • Full-length enzyme conformation not resolved
    • Substrate-bound state not visualized
  3. 2004 High

    Identifying TβRI degradation in cooperation with Smad7 placed WWP1 as a negative regulator of TGF-β signaling and distinguished it from Smurf ligases.

    Evidence Co-IP, reporter, nuclear export, and ubiquitination assays in mammalian cells

    PMID:15221015

    Open questions at the time
    • Linkage type on TβRI not yet defined
    • Mechanism of Smad7-dependent activation not yet structural
  4. 2005 High

    Reconstitution of KLF5 ubiquitination established the WW–PY recognition logic and the requirement for the catalytic cysteine.

    Evidence In vitro binding, ubiquitination assay, PY-motif and catalytic-cysteine mutagenesis

    PMID:16223724

    Open questions at the time
    • Cellular contexts of KLF5 regulation not yet mapped
  5. 2008 High

    Demonstration that the C2 domain restricts HER4 ubiquitination to membrane species and that WWP1 acts on viral PPPY motifs broadened the substrate logic to subcellular targeting and host-pathogen budding.

    Evidence Ubiquitination and domain-deletion assays on HER4; VLP budding assays for HTLV-1 Gag; NMR of WW4 with Nogo-A

    PMID:17609263 PMID:19035836 PMID:19047365

    Open questions at the time
    • In vivo relevance of viral cofactor role not established
    • Linkage types not always defined
  6. 2010 Medium

    Discovery of K63-linked, non-degradative ubiquitination of ΔNp63 showed WWP1 outputs are not limited to proteasomal turnover.

    Evidence Linkage-specific ubiquitination assay, reporter, and knockdown in keratinocytes

    PMID:20951678

    Open questions at the time
    • Mechanism by which K63 chains enhance transcription unresolved
  7. 2011 High

    Genetic knockout and competitive-binding studies positioned WWP1 in osteoblast differentiation (JunB degradation) and showed substrate access can be blocked by competing PY-motif binders such as TAZ.

    Evidence Wwp1 KO mice with rescue, ubiquitination assays, and competitive Co-IP/xenograft

    PMID:21795702 PMID:21809421 PMID:22045023

    Open questions at the time
    • Whether competition operates broadly across substrates not tested
    • p27 senescence role mechanistically distinct from differentiation role
  8. 2013 High

    A burst of substrate identification (TRAF6, AMPKα2, LATS1) and the multi-monoubiquitination of KLF in C. elegans extended WWP1 into innate immunity, metabolism, Hippo signaling, and longevity.

    Evidence Linkage-specific ubiquitination assays, KO/epistasis in mouse and C. elegans, cytokine and proliferation readouts

    PMID:23293026 PMID:23553732 PMID:23573293 PMID:23799152 PMID:24805825

    Open questions at the time
    • Tissue specificity of competing substrate networks unclear
    • Conditions selecting linkage type per substrate not defined
  9. 2015 High

    Defining C2/WW–HECT autoinhibition and its relief by Smad7 or cancer mutation provided the regulatory switch governing mono- versus poly-ubiquitination output.

    Evidence Domain-deletion, stability, and ubiquitination assays with cancer-variant characterization; WWP2/WWP1 heterodimer switch via PPM1G

    PMID:25071155 PMID:26152726

    Open questions at the time
    • Physiological signals triggering de-repression beyond Smad7 not fully enumerated
    • Structural basis of autoinhibition not solved
  10. 2018 Medium

    Disease alleles (chicken R440Q muscular dystrophy) and neuronal double-knockout studies linked WWP1 hyperactivation to substrate (β-dystroglycan) degradation and to axon-dendrite polarity.

    Evidence Competitive-binding/ubiquitination assays for β-dystroglycan; conditional Wwp1/Wwp2 double KO with in utero electroporation

    PMID:29635000 PMID:30392800

    Open questions at the time
    • Wwp1-specific contribution in the double-KO neuronal phenotype not resolved
    • Mechanistic basis of R440Q autoinhibition loss only partly defined
  11. 2019 High

    Identifying PTEN as a WWP1 substrate whose ubiquitination blocks dimerization/membrane recruitment, driven transcriptionally by MYC, established WWP1 as a central oncogenic node and a druggable target.

    Evidence WWP1 KO mice, I3C pharmacology, in vitro ubiquitination, PTEN dimerization/localization assays, MYC ChIP; plus KLF15 in diabetic muscle atrophy

    PMID:30830866 PMID:31097636

    Open questions at the time
    • Linkage architecture on PTEN not fully detailed
    • Selectivity/mechanism of I3C inhibition incomplete
  12. 2020 High

    Germline gain-of-function WWP1 variants in patients causally linked enzyme hyperactivation to PTEN inactivation and constitutive PI3K signaling, translating the WWP1–PTEN axis to human disease.

    Evidence In vitro ubiquitination, murine models, PI3K analysis, prospective patient cohort

    PMID:32459922

    Open questions at the time
    • Spectrum of clinical phenotypes not fully characterized
    • Whether all variants act solely via PTEN unknown
  13. 2021 High

    Cardiac, ciliary, junctional, and metabolic studies revealed linkage-specific outputs (K27 on DVL2, K48 on KLF15/Cx43, monoubiquitination of AMOTL2) and discrete subcellular pools regulating hypertrophy, Hedgehog, and Hippo signaling.

    Evidence MS interactome, linkage-specific ubiquitination, KO/AAV cardiac models, ciliary localization screen, junctional imaging with Crumbs

    PMID:26386426 PMID:34139860 PMID:34161574 PMID:34404733 PMID:34907909

    Open questions at the time
    • What dictates linkage choice per target not mechanistically resolved
    • Coordination among distinct subcellular pools unknown
  14. 2025 High

    Recent work defined site-specific and linkage-specific regulation of TXNIP, JARID1B, HIPK3, SHARP1, and NLRP3, and identified upstream transcriptional/translational regulators (MYC, C/EBPβ, YTHDF1) and a USP13 stabilizing loop, embedding WWP1 in cancer chemosensitivity, inflammation, and metabolic disease.

    Evidence Linkage- and site-specific ubiquitination assays, proteomics, RNA-seq/ChIP-seq, ChIP/reporter, deubiquitination assays

    PMID:35508474 PMID:39364720 PMID:40280416 PMID:40280477 PMID:40319251 PMID:40627385

    Open questions at the time
    • How a single enzyme partitions among these competing substrates in vivo is unresolved
    • Hierarchy of transcriptional/translational/DUB regulators not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how WWP1 selects ubiquitin linkage type (K48 vs K63 vs K27 vs mono) and which substrate it acts on in a given cellular context, and no full-length structural model integrates autoinhibition, cofactor activation, and linkage specificity.
  • No structural basis for linkage selection
  • No systematic map of substrate competition in vivo
  • Determinants of subcellular pool partitioning unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0031386 protein tag activity 8 GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 3 GO:0008289 lipid binding 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0005929 cilium 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2
Partners
AMOTL2DVL2KLF5PTCH1PTENSMAD7TRAF6USP13
Complex memberships
WWP2/WWP1 heterodimer

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Crystal structure of the WWP1 HECT domain reveals a two-lobed architecture similar to E6AP but with a different relative orientation of N and C lobes due to rotation about a polypeptide hinge; mutational analyses demonstrate that conformational flexibility at this hinge is essential for catalytic ubiquitin ligation activity. X-ray crystallography and active-site mutagenesis Molecular Cell High 12535537
2000 Murine Wwp1 encodes a broadly expressed protein containing a C2 domain, four WW domains, and a catalytic HECT domain; disruption of the C. elegans ortholog CeWWP1 by RNAi causes embryonic lethality with abnormal morphogenesis, establishing a non-redundant essential function in embryogenesis. RNAi knockdown in C. elegans; domain structure analysis by cloning Gene Medium 10903445
2001 WWP1 was identified as a binding partner for the autoinhibitory domain of KLF2/LKLF via yeast two-hybrid; in mammalian cells WWP1 functions as a co-factor that suppresses KLF2 transcriptional activation by binding its inhibitory subdomain. Yeast two-hybrid, mammalian co-expression transcriptional reporter assays Journal of Biological Chemistry Medium 11375995
2002 WWP1 generates at least six isoforms through alternative splicing that affect its domain structure, producing forms that contain or lack an N-terminal C2 domain; relative ratios of isoforms vary in a tissue-specific manner. RT-PCR, sequence analysis of cDNA clones Biochemical and Biophysical Research Communications Medium 11779188
2004 WWP1 associates with Smad7 and, in cooperation with Smad7, induces nuclear export of Smad7, enhances Smad7 binding to TGF-β type I receptor, and promotes ubiquitination and degradation of TβRI, thereby inhibiting Smad2 phosphorylation and TGF-β transcriptional responses. Unlike Smurf1/2, WWP1 does not ubiquitinate R-Smads or SnoN. Co-immunoprecipitation, reporter gene assays, ubiquitination assays, Western blot in mammalian cells Oncogene High 15221015
2005 WWP1 forms a protein complex with KLF5 in vivo and in vitro, mediates ubiquitination and proteasomal degradation of KLF5, and the catalytic cysteine of WWP1 is essential for this activity; a PY motif in the KLF5 transactivation domain is required for the interaction. Co-immunoprecipitation, in vitro binding assay, ubiquitination assay, mutagenesis, siRNA knockdown Journal of Biological Chemistry High 16223724
2006 WWP1 associates with p53, induces p53 ubiquitylation, and increases p53 stability while promoting its cytoplasmic accumulation and decreasing its transcriptional activity; these effects are independent of Mdm2. A reciprocal feedback exists whereby p53 reduces WWP1 expression. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, reporter assay, Western blot Oncogene Medium 16924229
2006 WWP1 nuclear localization is regulated by coexpression of human Notch1: coexpression of hN1 depletes WWP1 from the nucleus to colocalize with hN1 in early endosomes, dependent on the WWP1 HECT domain; WWP1 interacts in vitro with the cytoplasmic domain of Notch1. Immunofluorescence/subcellular fractionation, in vitro binding assay Molecular Membrane Biology Medium 16785210
2007 WWP1 interacts with the PPPY motif in the HTLV-1 Gag matrix domain, promotes ubiquitination of MA at lysine 74, and this ubiquitination facilitates viral particle assembly and budding; a dominant-negative WWP1 lacking the HECT domain inhibits particle release. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, virus-like particle budding assays Journal of Virology High 17609263
2008 WWP1 ubiquitinates and degrades HER4/ErbB4 (preferring membrane-localized Cyt1 isoform over nuclear s80 fragment) via binding to its PY motifs, especially the Cyt1-exclusive PY2 motif; the C2 membrane-association domain of WWP1 restricts its activity to membrane HER4 species; WWP1 expression diminishes HER4 biological activity. Co-immunoprecipitation, ubiquitination assay, domain deletion mutagenesis, cell-based overexpression/knockdown Molecular and Cellular Biology High 19047365
2008 A missense mutation (R440Q) in WWP1 is responsible for chicken muscular dystrophy; the mutation was found exclusively in dystrophic chickens. Sequence comparison, gene expression analysis, comparative genomics FEBS Letters Medium 18501710
2008 WWP1 was identified as a novel interacting partner for Nogo-A both in vitro and in vivo, binding via the Nogo-A PPxY motif to all four WWP1 WW domains; NMR solution structure of WW4 domain was determined and binding-perturbed residues mapped, yielding a structural complex model. Co-immunoprecipitation, ITC, CD, NMR (HSQC titration, structure determination), HADDOCK modeling Biochemistry High 19035836
2009 Endogenous spartin (SPG20) interacts via its PPXY motif with WWP1 (AIP5) WW domains; the PPXY motif and WWP1 are not required for spartin ubiquitination, suggesting spartin acts as an adaptor for WWP1. Co-immunoprecipitation, pulldown assay, subcellular fractionation Biochemical Journal Medium 19580544
2010 WWP1 E3 ligase binds specifically to ΔNp63 isoform and ubiquitinates it through Lys63-linked polyubiquitin chains without triggering proteasomal degradation; this K63 ubiquitination increases ΔNp63-dependent transcription. Depletion of WWP1 in keratinocytes induces cell cycle arrest. Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, siRNA knockdown, reporter assay Biochemical and Biophysical Research Communications Medium 20951678
2011 TAZ interacts with KLF5 through its WW domain at the KLF5 PY motif (the WWP1 binding site), thereby competing with WWP1 for KLF5 binding, inhibiting WWP1-KLF5 interaction and WWP1-mediated KLF5 ubiquitination and degradation; this competition stabilizes KLF5 to promote breast cell proliferation. Co-immunoprecipitation, ubiquitination assay, mutagenesis, siRNA knockdown, xenograft model Carcinogenesis High 22045023
2011 WWP1 promotes ubiquitination and degradation of JunB in mesenchymal stem cells; TNF-induced increase in Wwp1 expression leads to increased JunB ubiquitination and impaired osteoblast differentiation; Wwp1 knockout completely blocks TNF-induced JunB ubiquitination and rescues osteoblast differentiation. Ubiquitination assay, Wwp1 knockout mice, siRNA knockdown, osteoblast differentiation assays Stem Cells High 21809421
2011 WWP1 delays cellular senescence by promoting Lys48-linked polyubiquitination and proteasomal degradation of p27(Kip1); overexpression of WWP1 delays senescence while knockdown leads to premature senescence through p27 accumulation. Ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, senescence assays Journal of Biological Chemistry Medium 21795702
2012 WWP1 ubiquitylates ezrin via PPVY(477) motif, without targeting it for proteasomal degradation; ezrin ubiquitylation by WWP1 upregulates Met/HGF receptor levels and enhances wound-healing responses to HGF, requiring the PPVY motif intact. Co-immunoprecipitation, ubiquitination assay, domain mutagenesis, cell migration (wound-healing) assay PLoS ONE Medium 22629406
2012 WWP1 knockdown in MDA-MB-231 breast cancer cells reduces CXCL12-induced CXCR4 lysosomal trafficking and degradation, leading to increased CXCR4-mediated cell migration and enhanced bone metastasis in vivo. shRNA knockdown, CXCR4 trafficking/lysosomal assays, in vivo intracardiac injection bone metastasis model Bone Medium 22266093
2013 WWP1 promotes LATS1 polyubiquitination and degradation through the 26S proteasome pathway, negatively regulating LATS1 stability; LATS1 degradation is critical for WWP1-induced increased cell proliferation in breast cancer cells. In vitro and in vivo ubiquitination assay, siRNA knockdown, overexpression, proliferation assay PLoS ONE Medium 23573293
2013 Wwp1 negatively regulates osteoblast migration and differentiation; Wwp1 knockout increases JunB and CXCR4 protein levels in BMSCs and enhances their migration toward CXCL12; knockdown of JunB in Wwp1-/- BMSCs returns Runx2 protein levels to wild-type, placing JunB upstream of Runx2 in the Wwp1 pathway. Wwp1 knockout mice, siRNA knockdown, ubiquitination assay, osteoblast differentiation/migration assays, epistasis experiment Journal of Bone and Mineral Research High 23553732
2013 WWP1 interacts with AMPKα2 (identified by yeast two-hybrid and confirmed by Co-IP) and promotes its ubiquitin-proteasome-mediated degradation under high glucose conditions; WWP1 knockdown blocks high-glucose-induced AMPKα2 downregulation. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor (MG132) treatment Journal of Biological Chemistry Medium 23293026
2013 WWP1 promotes K48-linked polyubiquitination and proteasomal degradation of TRAF6 (but not IRAK1) in LPS-stimulated cells, thereby negatively regulating TLR4-mediated NF-κB/MAPK activation and pro-inflammatory cytokine (TNF-α and IL-6) production. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, cytokine ELISA PLoS ONE Medium 23799152
2014 The C. elegans Krüppel-like factor KLF-1 is a substrate for WWP-1-mediated multiple monoubiquitylation in vitro and in vivo; KLF-1 is essential for dietary-restriction-induced longevity acting downstream of WWP-1 in the same pathway (epistasis: klf-1 knockdown suppresses wwp-1 overexpression-extended lifespan; klf-1 intestinal overexpression requires wwp-1). In vitro ubiquitination assay, genetic epistasis in C. elegans, lifespan assays, in vivo co-immunoprecipitation Nature Communications High 24805825
2014 WWP2 heterodimerizes with WWP1; WWP1 in the WWP2/WWP1 heterodimer specifically ubiquitinates and degrades ΔNp73, while monomeric WWP2 degrades p73; the phosphatase PPM1G acts as a functional switch controlling the ratio of monomeric WWP2 to WWP2/WWP1 heterodimer, thereby regulating the balance between cellular p73 and ΔNp73 levels. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, phosphatase functional assay Molecular and Cellular Biology High 25071155
2015 WWP1 is autoinhibited through intramolecular interactions between its C2 and/or WW domains and the HECT domain, favoring monoubiquitination over polyubiquitination of TβRI; Smad7 binding to WWP1 disrupts this autoinhibition, switching WWP1 toward polyubiquitination activity and driving degradation of both TβRI and WWP1 itself. A cancer-derived WWP1 point mutation found in prostate cancer relieves C2/WW inhibition, causing WWP1 hyperactivation and excessive TβRI degradation. Domain deletion analysis, ubiquitination assay, mutagenesis, pulse-chase/stability assays, cancer variant functional characterization Journal of Biological Chemistry High 26152726
2015 Cardiomyocyte-specific overexpression of Wwp1 in mice causes ~90% reduction in cardiac Cx43 protein levels, left ventricular hypertrophy, and lethal ventricular arrhythmias; Wwp1 co-immunoprecipitates with and ubiquitylates Cx43 in cell-based assays, causing reduction in Cx43 steady-state levels. Transgenic mouse model, cardiomyocyte-specific overexpression, echocardiography, Co-immunoprecipitation, ubiquitination assay Journal of Molecular and Cellular Cardiology High 26386426
2016 WWP1 promotes K63-linked ubiquitination of mutant huntingtin (mHtt at Lys-63), which inhibits proteasomal degradation of mHtt and promotes aggregate formation and cell toxicity in HD models; WWP1 expression is upregulated in mHtt-expressing cells and colocalizes with mHtt aggregates. In vitro and in vivo ubiquitination assay (K63-linkage specific), cell toxicity assay, co-localization imaging Brain Research Medium 27107943
2017 WWP1 interacts with Ebola virus VP40 via the PPXY L-domain motif of VP40 (WW domain 1 of WWP1 being most critical); WWP1 ubiquitinates VP40, and this ubiquitination enhances VLP egress and decreases higher-molecular-weight oligomers of eVP40; enzymatically inactive WWP1-C890A mutant neither ubiquitinates VP40 nor enhances egress. Peptide pulldown, co-immunoprecipitation, siRNA knockdown, VLP budding assay, mutagenesis Journal of Virology High 28768865
2018 Sox9 transcription factor induces transcription of Wwp1 and Wwp2 loci in developing neurons; Wwp1 and Wwp2 double knockout causes defects in axon-dendrite polarity and aberrant laminar cortical distribution in pyramidal neurons; the downstream pathway involves miR-140 (encoded in Wwp2 intron) and Fyn kinase. Conditional double knockout mice, in utero electroporation, immunofluorescence, epistasis analysis Neuron Medium 30392800
2018 WWP1 R440Q missense mutation (chicken muscular dystrophy allele) increases ubiquitin ligase-mediated ubiquitination of both β-dystroglycan and WWP1 itself; the mutation decreases intramolecular HECT domain-mediated autoinhibition. Dystrophin and utrophin protect β-dystroglycan from WWP1-mediated degradation by competing for the shared binding site at the cytosolic tail of β-dystroglycan. Co-immunoprecipitation, ubiquitination assay, mutagenesis, competitive binding assay Biochimica et Biophysica Acta - Molecular Basis of Disease High 29635000
2019 WWP1-mediated polyubiquitination suppresses PTEN dimerization, membrane recruitment, and phosphatase function; genetic ablation or pharmacological inhibition of WWP1 with indole-3-carbinol (I3C) reactivates PTEN tumor-suppressive activity; WWP1 is a direct MYC transcriptional target gene and is critical for MYC-driven tumorigenesis. Genetic ablation (WWP1 KO mice), pharmacological inhibition (I3C), in vitro ubiquitination assay, PTEN dimerization/membrane localization assays, ChIP for MYC-WWP1 promoter binding Science High 31097636
2019 Hyperglycemia downregulates WWP1 in skeletal muscle, causing accumulation of KLF15 protein (normally degraded by WWP1-mediated ubiquitination); elevated KLF15 then induces muscle atrophy genes. Muscle-specific KLF15 knockout mice are protected from diabetes-induced loss of skeletal muscle mass. Diabetic model mice, muscle-specific KLF15 KO, Western blot, ubiquitination assay JCI Insight High 30830866
2020 Germline gain-of-function WWP1 variants (e.g., K740N, N745S) result in aberrant enzymatic activation causing enhanced PTEN polyubiquitination and functional inactivation, triggering hyperactive PI3K signaling; confirmed in cellular and murine in vivo models. In vitro ubiquitination assay, murine in vivo models, PI3K signaling analysis, prospective patient cohort New England Journal of Medicine High 32459922
2021 WWP1 directly interacts with DVL2 (disheveled segment polarity protein 2) and promotes K27-linked polyubiquitination of DVL2, stabilizing it; stabilized DVL2 activates the CaMKII/HDAC4/MEF2C pathway to exacerbate pressure overload-induced cardiac hypertrophy; WWP1 knockout protects the heart from TAC-induced hypertrophy. Mass spectrometry (interactome), Co-immunoprecipitation, ubiquitination assay (K27-linkage), pulse-chase assay, WWP1 KO mice, AAV9 cardiac gene transfer, echocardiography Circulation High 34139860
2021 WWP1 triggers K48-linked polyubiquitination and proteasomal degradation of KLF15 in cardiomyocytes; WWP1-mediated KLF15 degradation leads to increased p65 acetylation and activation of MAPK inflammatory signaling, contributing to ischemic myocardial injury after MI. Adenovirus/AAV overexpression system, Co-immunoprecipitation, ubiquitination assay (K48-linkage), rAAV9 gene transfer mice, echocardiography, pharmacological inhibition with I3C Theranostics High 36593958
2021 WWP1 localizes to primary cilia and binds Ptch1; at basal state, ciliary WWP1 maintains low ciliary levels of Smo (Hedgehog receptor); Hedgehog pathway activation removes both Ptch1 and WWP1 from cilia, providing a mechanism by which Ptch1 regulates ciliary Smo levels through ubiquitination. Focused genetic screen of ubiquitin-related genes, immunofluorescence/ciliary localization, co-immunoprecipitation Journal of Cell Biology Medium 34161574
2021 WWP1 mono-ubiquitinates AMOTL2 at K347 and K408; mono-ubiquitinated AMOTL2 interacts with LATS2 kinase, facilitating SAV1 recruitment and YAP phosphorylation/inactivation to promote contact inhibition; high cell density induces localization of WWP1 to cell junctions where it interacts with Crumbs polarity proteins required for AMOTL2 mono-ubiquitination. Ubiquitination assay (monoubiquitination), site-directed mutagenesis, Co-immunoprecipitation, immunofluorescence localization, Hippo pathway readouts Life Science Alliance Medium 34404733
2021 WWP1 inactivation restores PTEN plasma membrane localization that is lost upon PI3K inhibitor treatment; WWP1 ubiquitinates AMPKα2, inhibiting its activatory phosphorylation; WWP1 inhibition facilitates AMPKα2 activity in muscle to compensate for glucose uptake reduction upon PI3K inhibition, thereby reducing hyperglycemia side effects. Genetic and pharmacological (I3C) WWP1 inhibition, PTEN membrane localization assays, AMPKα2 ubiquitination assay, phosphorylation analysis, in vitro and in vivo tumor growth assays Journal of Clinical Investigation High 34907909
2022 WWP1 promotes K48-linked ubiquitination and proteasomal degradation of NLRP3, thereby inhibiting caspase-1-dependent pyroptosis; the m6A reader YTHDF1 promotes WWP1 translation, and overexpression of YTHDF1 or WWP1 inhibits NLRP3 inflammasome activation in sepsis models. Immunoprecipitation ubiquitination assay, meRIP assay, RIP-RT-qPCR, gain/loss-of-function in vitro and in vivo (CLP model), Western blot Cell Death Discovery Medium 35508474
2024 USP13 deubiquitinase directly interacts with WWP1 and removes K29- and K48-linked polyubiquitin chains from WWP1, stabilizing it via the ubiquitin-proteasome pathway; YY1 transcription factor upregulates both USP13 and WWP1 expression. Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assay, ubiquitination assay with linkage-specific analysis Cellular & Molecular Biology Letters Medium 40319251
2024 WWP1 directly interacts with TXNIP and promotes its K48-linked ubiquitin-dependent proteasomal degradation in AML cells; WWP1 inactivation leads to TXNIP accumulation, reduced thioredoxin activity, increased ROS, DNA strand breaks, impaired glucose uptake, and apoptosis. Co-immunoprecipitation, ubiquitination assay, ROS measurement, glucose uptake assay, siRNA knockdown Molecular Oncology Medium 39364720
2025 WWP1 promotes K63-linked polyubiquitination of JARID1B (KDM5B) histone demethylase, stabilizing it (non-degradative ubiquitination); WWP1 inactivation causes JARID1B downregulation, increased H3K4me3 at JARID1B target genes, defective DNA damage repair factor recruitment, and enhanced chemosensitivity of AML cells. Proteomic analysis, Co-immunoprecipitation, K63-linked ubiquitination assay, RNA-seq, H3K4me3 ChIP-seq, DNA damage repair assays PNAS High 40627385
2025 WWP1 directly interacts with HIPK3 and promotes K48-linked polyubiquitination at K1187, leading to HIPK3 proteasomal degradation; the WWP1/HIPK3 axis modulates cancer cell chemosensitivity through regulation of JNK signaling; MYC acts as a transcription factor enhancing WWP1 expression. Co-immunoprecipitation, ubiquitination assay (K48-linkage, site-specific mutagenesis), JNK signaling analysis, ChIP/reporter for MYC-WWP1 Journal of Biological Chemistry Medium 40280416
2025 WWP1 ubiquitinates and degrades SHARP1 via its WW3 domain and catalytic HECT domain; C/EBPβ binds the WWP1 promoter and upregulates WWP1 expression in response to fatty acid treatment, creating a positive feedback loop that accelerates MASLD progression. Co-immunoprecipitation, ubiquitination assay, domain mutagenesis (WWP1-C886A, C890A, ΔWW3), ChIP, luciferase reporter assay Metabolism Medium 40280477
2024 WWP1 localizes to the Golgi apparatus via its C2 domain in adipocytes, protecting Golgi morphology from disruption; WWP1 overexpression increases chondroitin sulfate and heparan sulfate proteoglycan levels, while knockdown decreases them. Immunofluorescence (Golgi localization), domain deletion analysis (C2 domain), monensin-induced disruption assay, proteoglycan quantification Scientific Reports Medium 39578509
2017 WWP1 sustains AML cell growth by promoting proteasomal degradation of p27Kip1; WWP1 inactivation causes p27Kip1 accumulation, G0/G1 arrest, and autophagy induction in leukemic blasts; WWP1-depleted AML cells show reduced leukemogenic potential in immunocompromised mice. siRNA knockdown, Western blot for p27 accumulation, cell cycle analysis, autophagy assay, in vivo transplantation model Leukemia Medium 29209041

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Molecular cell 239 12535537
2019 Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science (New York, N.Y.) 234 31097636
2004 Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene 166 15221015
2019 Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis. JCI insight 164 30830866
2011 Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem cells (Dayton, Ohio) 135 21809421
2005 Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. The Journal of biological chemistry 122 16223724
2007 The amplified WWP1 gene is a potential molecular target in breast cancer. International journal of cancer 120 17330240
2011 WWP1: a versatile ubiquitin E3 ligase in signaling and diseases. Cellular and molecular life sciences : CMLS 111 22051607
2006 Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 110 16924229
2006 Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene 108 17016436
2021 CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway. Molecular cancer 98 33648498
2011 TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis. Carcinogenesis 81 22045023
2021 Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination. Circulation 80 34139860
2022 YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis. Cell death discovery 73 35508474
2013 WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells. PloS one 71 23573293
2020 WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition. The New England journal of medicine 65 32459922
2009 Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5. The Biochemical journal 61 19580544
2018 Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140. Neuron 58 30392800
2013 Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 58 23553732
2001 Lung Krüppel-like factor contains an autoinhibitory domain that regulates its transcriptional activation by binding WWP1, an E3 ubiquitin ligase. The Journal of biological chemistry 57 11375995
2021 miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/β-catenin signaling pathway. Experimental & molecular medicine 55 34035464
2016 Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer. British journal of cancer 55 27070713
2023 Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation. Theranostics 52 36593958
2010 WWP-1 is a novel modulator of the DAF-2 insulin-like signaling network involved in pore-forming toxin cellular defenses in Caenorhabditis elegans. PloS one 51 20209166
2011 WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) delays cellular senescence by promoting p27(Kip1) degradation in human diploid fibroblasts. The Journal of biological chemistry 47 21795702
2007 Nucleotide excision repair and the degradation of RNA pol II by the Caenorhabditis elegans XPA and Rsp5 orthologues, RAD-3 and WWP-1. DNA repair 44 18053776
2015 MiR-21 suppresses endothelial progenitor cell proliferation by activating the TGFβ signaling pathway via downregulation of WWP1. International journal of clinical and experimental pathology 43 25755729
2014 Knockdown of WWP1 inhibits growth and induces apoptosis in hepatoma carcinoma cells through the activation of caspase3 and p53. Biochemical and biophysical research communications 43 24792179
2017 Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress. Journal of virology 42 28768865
2019 Polarisome scaffolder Spa2-mediated macromolecular condensation of Aip5 for actin polymerization. Nature communications 41 31699995
2015 Cardiomyocyte-specific overexpression of the ubiquitin ligase Wwp1 contributes to reduction in Connexin 43 and arrhythmogenesis. Journal of molecular and cellular cardiology 41 26386426
2008 The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation. Molecular and cellular biology 41 19047365
2017 The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia. Leukemia 40 29209041
2014 WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 25293520
2009 Overexpression of WWP1 is associated with the estrogen receptor and insulin-like growth factor receptor 1 in breast carcinoma. International journal of cancer 40 19267401
2012 The ubiquitin E3 ligase WWP1 decreases CXCL12-mediated MDA231 breast cancer cell migration and bone metastasis. Bone 37 22266093
2010 The E3 ubiquitin ligase WWP1 regulates ΔNp63-dependent transcription through Lys63 linkages. Biochemical and biophysical research communications 36 20951678
2021 The emerging role of WWP1 in cancer development and progression. Cell death discovery 35 34226507
2016 Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant huntingtin. Brain research 34 27107943
2014 Bortezomib prevents oncogenesis and bone metastasis of prostate cancer by inhibiting WWP1, Smurf1 and Smurf2. International journal of oncology 34 25051198
2021 E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened. The Journal of cell biology 33 34161574
2014 WWP2-WWP1 ubiquitin ligase complex coordinated by PPM1G maintains the balance between cellular p73 and ΔNp73 levels. Molecular and cellular biology 33 25071155
2002 Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. Biochemical and biophysical research communications 33 11779188
2000 A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis. Gene 33 10903445
2018 miR-129-5p and -3p co-target WWP1 to suppress gastric cancer proliferation and migration. Journal of cellular biochemistry 32 30417502
2007 The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1. Journal of virology 32 17609263
2023 WWP1 E3 ligase at the crossroads of health and disease. Cell death & disease 30 38129384
2013 WW domain containing E3 ubiquitin protein ligase 1 (WWP1) negatively regulates TLR4-mediated TNF-α and IL-6 production by proteasomal degradation of TNF receptor associated factor 6 (TRAF6). PloS one 30 23799152
2014 A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans. Nature communications 29 24805825
2013 E3 ubiquitin ligase, WWP1, interacts with AMPKα2 and down-regulates its expression in skeletal muscle C2C12 cells. The Journal of biological chemistry 29 23293026
2019 Small Nucleolar RNA Host Gene 12 (SNHG12) Promotes Proliferation and Invasion of Laryngeal Cancer Cells via Sponging miR-129-5p and Potentiating WW Domain-Containing E3 Ubiquitin Protein Ligase 1 (WWP1) Expression. Medical science monitor : international medical journal of experimental and clinical research 27 31348766
2011 The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer. International journal of cancer 27 21480222
2021 BAP1 antagonizes WWP1-mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression. Experimental cell research 25 33516665
2021 WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models. The Journal of clinical investigation 24 34907909
2019 A positive feedback loop of miR-30a-5p-WWP1-NF-κB in the regulation of glioma development. The international journal of biochemistry & cell biology 22 30978403
2018 Selection and Characterization of a DNA Aptamer Specifically Targeting Human HECT Ubiquitin Ligase WWP1. International journal of molecular sciences 22 29518962
2013 WWP1 gene is a potential molecular target of human oral cancer. Oral surgery, oral medicine, oral pathology and oral radiology 22 23849376
2008 The ubiquitin ligase gene (WWP1) is responsible for the chicken muscular dystrophy. FEBS letters 22 18501710
2022 α-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics 20 35154481
2008 Identification and structural mechanism for a novel interaction between a ubiquitin ligase WWP1 and Nogo-A, a key inhibitor for central nervous system regeneration. Biochemistry 20 19035836
2006 Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch. Molecular membrane biology 19 16785210
2023 Biomimetic composite hydrogel promotes new bone formation in rat bone defects through regulation of miR-19b-3p/WWP1 axis by loaded extracellular vesicles. Journal of nanobiotechnology 17 38037135
2020 MicroRNA-15b shuttled by bone marrow mesenchymal stem cell-derived extracellular vesicles binds to WWP1 and promotes osteogenic differentiation. Arthritis research & therapy 17 33198785
2015 Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer. The Journal of biological chemistry 16 26152726
2015 Knockdown of WWP1 inhibits growth and invasion, but induces apoptosis of osteosarcoma cells. International journal of clinical and experimental pathology 16 26339351
2021 WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity. Frontiers in cell and developmental biology 15 34733849
2012 Ezrin ubiquitylation by the E3 ubiquitin ligase, WWP1, and consequent regulation of hepatocyte growth factor receptor activity. PloS one 14 22629406
2025 YY1 induced USP13 transcriptional activation drives the malignant progression of hepatocellular carcinoma by deubiquitinating WWP1. Cellular & molecular biology letters 13 40319251
2020 WWP1 knockout in mice exacerbates obesity-related phenotypes in white adipose tissue but improves whole-body glucose metabolism. FEBS open bio 13 31965758
2018 Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes. Biochemical and biophysical research communications 13 30471861
2018 β-dystroglycan is regulated by a balance between WWP1-mediated degradation and protection from WWP1 by dystrophin and utrophin. Biochimica et biophysica acta. Molecular basis of disease 12 29635000
2003 Differential expression and localisation of WWP1, a Nedd4-like protein, in epithelia. Pflugers Archiv : European journal of physiology 12 12908109
2019 YFR016c/Aip5 is part of an actin nucleation complex in yeast. Biology open 11 31362951
2024 Extrachromosomal circular DNA promotes prostate cancer progression through the FAM84B/CDKN1B/MYC/WWP1 axis. Cellular & molecular biology letters 10 38997648
2021 RETRACTED ARTICLE: METTL3-mediated mature miR-497-5p/195-5p inhibits trophoblast migration and invasion by targeting WWP1 in preeclampsia. Cell cycle (Georgetown, Tex.) 10 34592887
2020 The ubiquitin ligase WWP1 contributes to shifts in matrix proteolytic profiles and a myocardial aging phenotype with diastolic heart. American journal of physiology. Heart and circulatory physiology 9 32822210
2024 The role of WWP1 and WWP2 in bone/cartilage development and diseases. Molecular and cellular biochemistry 8 38252355
2021 Ubiquitin ligase Wwp1 gene deletion attenuates diastolic dysfunction in pressure-overload hypertrophy. American journal of physiology. Heart and circulatory physiology 8 34559578
2025 RTA-408 overcomes cisplatin-resistant lung cancer by inhibiting WWP1-mediated NCOA4 ubiquitination to induce ferritinophagy and ferroptosis. Free radical biology & medicine 7 40645461
2024 WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer. NPJ precision oncology 7 39014007
2021 High Expression of WWP1 Associates with Tumor Progression in Papillary Thyroid Cancer. Cancer biotherapy & radiopharmaceuticals 7 34388030
2021 A teamwork promotion of formin-mediated actin nucleation by Bud6 and Aip5 in Saccharomyces cerevisiae. Molecular biology of the cell 7 34818061
2017 DNA damage induces expression of WWP1 to target ΔNp63α to degradation. PloS one 7 28426804
2023 Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice. FEBS open bio 6 37032433
2024 Thioredoxin-interacting protein (TXNIP) is a substrate of the NEDD4-like E3 ubiquitin-protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells. Molecular oncology 5 39364720
2024 N-butanol extract of Broussonetia papyrifera (L.) L'Hér. ex Vent root bark alleviates atopic dermatitis by targeting E3 ubiquitin ligase WWP1 to promote NLRP3 degradation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 39405906
2024 WWP1 targeting PTEN for polyubiquitination to promote bone metastasis of luminal breast cancer. Scientific reports 5 39622957
2025 WWP1-SHARP1-C/EBPβ positive feedback loop modulates development of metabolic dysfunction-associated steatotic liver disease. Metabolism: clinical and experimental 4 40280477
2021 AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation. Life science alliance 4 34404733
2011 Exclusion of WWP1 mutations in a cohort of dystroglycanopathy patients. Muscle & nerve 4 21996799
2025 The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance. Proceedings of the National Academy of Sciences of the United States of America 3 40627385
2023 Molecular mechanism of WWP1-mediated ubiquitination modification affecting proliferation and invasion/migration of liver cancer cells. The Kaohsiung journal of medical sciences 3 37997542
2020 [WWP1 promotes cell proliferation in hepatocellular carcinoma through ubiquitin-degradation EI24]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 3 32252198
2025 Portrait of WWP1: the current state in human cancer. Frontiers in cell and developmental biology 2 39949609
2025 Aip5 forms a "composite" actin nucleator with Bud6 and caps pointed ends of actin filaments. The Journal of cell biology 2 41065574
2024 The effects of WWP1 overexpression on the golgi apparatus stress response and proteoglycan production in adipocytes. Scientific reports 2 39578509
2022 Bone marrow mesenchymal stem cell-derived extracellular vesicles facilitate endometrial injury repair by carrying the E3 ubiquitin ligase WWP1. Biochemistry and cell biology = Biochimie et biologie cellulaire 2 36043683
2021 Molecular docking data of E3 ubiquitin-protein ligase WWP1 with compounds from a medicinal plant Justicia adhatoda L. Bioinformation 2 34393432
2025 WWP1 mediates the ubiquitination and degradation of HIPK3 in bladder cancer cells. The Journal of biological chemistry 1 40280416
2024 Immunohistochemical Expression and Clinical Significance of WWP1 Protein in Nasopharyngeal Cancer. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 1 38804681

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