Affinage

WWP2

NEDD4-like E3 ubiquitin-protein ligase WWP2 · UniProt O00308

Length
870 aa
Mass
98.9 kDa
Annotated
2026-06-11
100 papers in source corpus 61 papers cited in narrative 61 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

WWP2 is a HECT-type E3 ubiquitin ligase that couples substrate recognition through its WW domains to ubiquitin transfer by its C-terminal HECT domain, controlling diverse developmental, transcriptional, immune, and stress-response programs through both proteolytic and non-proteolytic ubiquitination (PMID:15047715, PMID:26457515). Its catalytic activity is held in cis-autoinhibition by the WW2,3-linker, and is relieved by adaptor proteins binding WW-domain PPxY motifs (Ndfips, Dvl2, ARRDC3) or by tyrosine phosphorylation of the linker at Y369 by ACK1 downstream of EGF, with linker phosphorylation also tuning ubiquitin chain linkage (K48 versus K63) (PMID:31578285, PMID:26701932, PMID:36773333, PMID:41135677). Through this machinery WWP2 catalyzes K48-linked degradative ubiquitination of substrates including PTEN, where it acts as the physiological in vivo ligase controlling AKT signaling, as well as RPB1, p73/ΔNp73, PARP1, LATS1/2, and pro-apoptotic and metabolic effectors such as BAK and SDHC (PMID:21532586, PMID:29685889, PMID:31048545, PMID:25071155, PMID:32139900). WWP2 also performs non-proteolytic mono-ubiquitination that activates transcription factors—Goosecoid, RUNX2, KLF5, and IRF7—and mono-ubiquitination of OCT4 that inactivates its transcriptional output, linking WWP2 to skeletal, craniofacial, and pluripotency programs (PMID:15047715, PMID:21170031, PMID:28500134, PMID:33164644, PMID:36450710). Three isoforms (full-length, N-terminal, C-terminal) differentially select substrates within the TGFβ/Smad axis, where nuclear N-terminal WWP2 drives SMAD2-dependent pro-fibrotic transcription (PMID:21258410, PMID:31399586). In DNA repair, WWP2 is recruited to double-strand breaks and ubiquitinates RPB1 to evict RNAPII and enable NHEJ (PMID:31048545), and across innate and adaptive immunity it degrades TRIF, modifies SHP-1 with Itch, and mono-ubiquitinates IRF7 to shape interferon and chemokine responses (PMID:23479606, PMID:29925997, PMID:36450710). Crystallographic and NMR structures of the HECT and WW4 domains provide the structural framework for these activities (PMID:26457515, PMID:31546607).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 High

    Established WWP2 as a functional E3 ligase and defined its first substrate, showing that WW-domain-mediated substrate recognition coupled to catalytic ubiquitination can regulate a transcription factor non-proteolytically.

    Evidence Co-IP, in vitro ubiquitination, catalytically inactive mutant, and reporter assays linking WWP2 to OCT4 mono-ubiquitination

    PMID:15047715

    Open questions at the time
    • Did not define WWP2 domain architecture controlling activity
    • Physiological context of OCT4 regulation unresolved at this stage
  2. 2007 High

    Showed WWP2 targets the RNAPII large subunit RPB1 via CTD binding, establishing a role in regulating the transcription machinery itself independent of phosphorylation state.

    Evidence Co-IP, in vitro ubiquitination, CTD lysine acceptor-site mapping, and RNAi knockdown in cells

    PMID:17526739

    Open questions at the time
    • Functional consequence beyond steady-state RPB1 levels not yet linked to a pathway
  3. 2008 High

    Revealed adaptor-bridged substrate selection, showing Ndfip proteins recruit WW-motif-lacking substrates like DMT1 to WWP2, expanding its substrate repertoire and connecting it to iron homeostasis.

    Evidence Co-IP, ubiquitination assay, and Ndfip1 KO mice with hepatic iron phenotype

    PMID:18776082

    Open questions at the time
    • Direct in vivo requirement for WWP2 (vs. Ndfip1) in iron handling not isolated
  4. 2011 High

    Defined WWP2 as a PTEN ligase controlling apoptosis and tumorigenicity, and resolved isoform-specific substrate selection within the TGFβ/Smad pathway, framing WWP2 as a context-dependent signaling regulator.

    Evidence Tandem affinity purification, in vitro ubiquitination, isoform Co-IP pairings, and TGFβ/EMT functional assays

    PMID:21258410 PMID:21427722 PMID:21532586 PMID:21847096

    Open questions at the time
    • In vivo physiological ligase identity for PTEN not yet established
    • Mechanism distinguishing degradative vs. activating ubiquitination unclear
  5. 2013 High

    Demonstrated WWP2 controls innate immunity by K48-degradation of TRIF, establishing a negative-regulatory role in TLR3 signaling with a defined cytokine phenotype.

    Evidence Biochemical purification, K48-linkage ubiquitination assay, and Wwp2 KO mice challenged with poly(I:C)

    PMID:23479606

    Open questions at the time
    • Upstream signal triggering WWP2-TRIF engagement not defined
  6. 2015 High

    Provided structural and regulatory frameworks: the HECT crystal structure plus discovery that the WW2,3-linker autoinhibits catalysis and that adaptor binding or linker phosphorylation tunes activity and chain linkage.

    Evidence X-ray crystallography of the HECT domain; in vitro ubiquitination with linker mutants, phosphomimics, NDFIP1, and ubiquitin variants

    PMID:26457515 PMID:31578285

    Open questions at the time
    • Full-length autoinhibited structure not solved
    • Physiological kinases driving linker phosphorylation not all identified
  7. 2016 Medium

    Identified upstream control of WWP2 activity by Cdh1 in an APC/C-independent manner, linking cell-cycle regulators to WWP2-driven PTEN turnover and PI3K/Akt signaling.

    Evidence Co-IP, ubiquitination assay, and Cdh1 KO/overexpression with PTEN readout

    PMID:27462441

    Open questions at the time
    • Mechanism of Cdh1 suppression of WWP2 not structurally defined
    • Single lab
  8. 2018 High

    Established WWP2 as the physiological in vivo PTEN ligase via genetic epistasis and revealed cooperative ligase complexes (with Itch) and developmental roles, distinguishing WWP2 from competing E3s.

    Evidence Conditional and double KO mouse models (WWP2/CHIP; Itch/WWP2); Co-IP and T-cell/neuronal phenotyping

    PMID:29685889 PMID:29925997 PMID:30392800

    Open questions at the time
    • Relative contributions of WWP2 vs. partner ligases to shared phenotypes incompletely separable
  9. 2019 High

    Connected WWP2 to DNA double-strand break repair through RPB1 eviction and defined activating regulatory inputs (ACK1 phosphorylation of Y369; WW4 phosphopeptide recognition of Smad7), while expanding its in vivo roles in cartilage and cardiac fibrosis.

    Evidence ChIP, K48-ubiquitination assay, non-ubiquitylatable RPB1 mutant, NHEJ assay; in vitro kinase/phosphomimetic assays; NMR of WW4; Wwp2 C838A knock-in and N-terminal transgenic mice

    PMID:31048545 PMID:31160553 PMID:31399586 PMID:31546607 PMID:36773333

    Open questions at the time
    • How WWP2 is recruited specifically to break-associated transcribed loci not fully resolved
    • Isoform-specific nuclear targeting mechanism incomplete
  10. 2021 High

    Generalized non-proteolytic activating ubiquitination to additional transcription factors (RUNX2, KLF5) and revealed competitive shielding of substrates by binding proteins (TRIM26 protecting SOX2), defining how substrate access is gated.

    Evidence Ubiquitination site mapping, active-site mutagenesis, reporter and differentiation assays; reciprocal Co-IP and competition ubiquitination assays

    PMID:28500134 PMID:33164644 PMID:34732716

    Open questions at the time
    • Determinants selecting mono- vs. poly-ubiquitination on different substrates not mechanistically defined
  11. 2022 High

    Extended WWP2 into autophagy and selective organelle quality control, ubiquitinating autophagy receptors and enabling mitophagy, and defined IRF7 mono-ubiquitination as a driver of monocyte recruitment in cardiac fibrosis.

    Evidence Protein microarray substrate discovery, MS site-mapping, CRISPR KO mitophagy rescue with Y369E; myeloid-specific KO with scRNA-seq

    PMID:35331737 PMID:36450710

    Open questions at the time
    • In vivo relevance of individual autophagy-receptor substrates not dissected
    • Phosphomimetic-driven substrate hits await endogenous validation
  12. 2025 Medium

    Mapped the disinhibition logic in detail—canonical Ndfip PY-motif activation versus co-disinhibitory pairs (TMEM127/SUSD6) and pathogen-effector hijacking (Salmonella SteD via its C2 domain)—and added subcellular and metabolic dimensions including mitochondrial SDHC degradation.

    Evidence Co-IP, in vitro activity assays with PY and domain mutants, infection models; mitochondrial fractionation and SDHC rescue in tubule-specific KO

    PMID:41135677 PMID:41254942

    Open questions at the time
    • Structural basis of co-disinhibitory pair activation not resolved
    • Mechanism of WWP2 mitochondrial shuttling undefined
    • Single lab for each axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WWP2 isoform expression, subcellular targeting, and linker phosphorylation are integrated to select among its very broad substrate set in a given physiological context remains unresolved.
  • No unifying model predicting substrate choice from activation state
  • Many disease-context substrates rest on single-lab Co-IP/ubiquitination evidence without reciprocal or in vivo confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
ITCHNDFIP1OCT4PTENRPB1SMAD7TRIFWWP1

Evidence

Reading pass · 61 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 WWP2 (Wwp2) is an E3 ubiquitin ligase that specifically interacts with Oct-4 via its WW domain and promotes Oct-4 ubiquitination both in vitro and in vivo; a catalytically inactive point mutant abolishes ubiquitination; monoubiquitination inactivates Oct-4 transcriptional activity; overexpression of WWP2 in embryonic stem cells reduces Oct-4 transcriptional activity. Co-IP, in vitro ubiquitination assay, catalytically-inactive mutant, reporter assay, ES cell overexpression The Journal of biological chemistry High 15047715
2007 Wwp2 interacts with the large subunit of RNA polymerase II (Rpb1) through its WW domain binding to Rpb1's CTD, and targets Rpb1 for ubiquitination both in vitro and in vivo in a manner independent of Rpb1 phosphorylation state and DNA damage; six lysine residues in the CTD are identified as ubiquitin acceptor sites; downregulation of Wwp2 elevates Rpb1 steady-state protein levels. Co-IP, in vitro ubiquitination assay, domain-mapping, RNAi knockdown, immunoblotting Molecular and cellular biology High 17526739
2009 Human WWP2 interacts with OCT4 through its WW domain and promotes ubiquitination and 26S proteasome-dependent degradation of OCT4; the active-site cysteine residue of WWP2 is required for both enzymatic activity and OCT4 proteolysis; RNAi knockdown of WWP2 in human ES cells elevates endogenous OCT4 protein levels. Co-IP, in vitro ubiquitination assay, active-site mutation (C→A), RNAi knockdown, proteasome inhibitor rescue Cell research High 19274063
2009 Wwp2 catalyzes Oct4 poly-ubiquitination via K63 linkage in a dosage-dependent manner during differentiation of embryonal carcinoma cells; Wwp2 also auto-ubiquitinates through an intramolecular mechanism; inhibition of Wwp2 by RNAi elevates endogenous Oct4 protein and attenuates retinoic acid-induced differentiation. In vitro ubiquitination assay with K63-only ubiquitin mutants, RNAi, immunoblotting Cell research High 19997087
2010 Wwp2 interacts with the transcription factor Goosecoid (Gsc) and catalyzes its mono-ubiquitylation; this non-proteolytic modification is required for optimal Gsc transcriptional activation of Sox6; Wwp2-deficient mice develop craniofacial malformations consistent with loss of this pathway. Co-IP, in vitro ubiquitination assay, Wwp2 KO mouse model, reporter assay Nature cell biology High 21170031
2011 WWP2 (also known as AIP-2) physically interacts with PTEN and mediates its poly-ubiquitination and proteasome-dependent degradation; WWP2 controls cellular apoptosis and is required for tumorigenicity; identified by tandem affinity purification. Tandem affinity purification, Co-IP, in vitro ubiquitination assay, cell-based degradation assay Nature cell biology High 21532586
2011 Wwp2 interacts physically with Sox9 and undergoes nuclear translocation to associate with Sox9 transcriptional activity; Wwp2 also interacts with Med25 (Mediator subunit 25), and Sox9 transcriptional activity is positively regulated by Wwp2 through the Sox9–Med25 interaction; morpholino knockdown of wwp2 or med25 in zebrafish phenocopies sox9 mutant palatal malformation. Yeast two-hybrid, Co-IP, morpholino knockdown in zebrafish, reporter assay Nature communications High 21427722
2011 Full-length WWP2 (WWP2-FL) interacts with Smad2, Smad3, and Smad7; the N-terminal isoform (WWP2-N) interacts with Smad2 and Smad3; the C-terminal isoform (WWP2-C) interacts only with Smad7; WWP2-FL and WWP2-C preferentially ubiquitinate and degrade Smad7; WWP2-N lacks the HECT domain but interacts with WWP2-FL to activate its ubiquitin ligase activity causing degradation of Smad2/3; these interactions differentially modulate TGFβ-dependent transcription and EMT. Co-IP, in vitro ubiquitination assay, overexpression and knockdown, TGFβ reporter assay, EMT functional assay Oncogene High 21258410
2011 The E3 ubiquitin ligase WWP2 (AIP2) binds to ADAR2 and catalyzes its ubiquitination and subsequent proteasome-dependent degradation, thereby reducing ADAR2 editing activity at the GluR2 Q/R site; this acts in opposition to Pin1, which promotes ADAR2 nuclear localization and stability. Co-IP, ubiquitination assay, Pin1−/− MEFs mislocalization, editing assay at GluR2 Q/R site The EMBO journal High 21847096
2008 WWP2 mediates ubiquitination and degradation of the divalent metal ion transporter DMT1; DMT1 lacks WW-binding motifs but interacts with adaptor proteins Ndfip1 and Ndfip2, which bridge DMT1 to WWP2; Ndfip1−/− mice show increased DMT1 activity and hepatic iron deposition, demonstrating Ndfip1's essential role in iron homeostasis through this pathway. Co-IP, ubiquitination assay, Ndfip1 KO mouse model with iron phenotype Blood High 18776082
2013 WWP2 was identified as a TRIF-associated protein by biochemical purification; WWP2 mediates K48-linked ubiquitination and proteasome-dependent degradation of TRIF upon TLR3 activation; Wwp2-deficient mice show elevated IFN-β, CCL5, TNFα, and IL-6 in response to poly(I:C) and increased susceptibility to poly(I:C)-induced death. Biochemical purification, Co-IP, K48-linked ubiquitination assay, Wwp2 KO mouse, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 23479606
2009 The HECT-type E3 ligase AIP2 (WWP2) interacts with EGR2 and promotes its ubiquitin-mediated degradation; AIP2 suppresses activation-induced T-cell death by reducing EGR2-mediated FasL expression; RNAi knockdown of AIP2 upregulates EGR2, inhibits its ubiquitination, and enhances T-cell apoptosis. Co-IP, ubiquitination assay, RNAi knockdown, T-cell proliferation/apoptosis assays Molecular and cellular biology High 19651900
2014 WWP2 ubiquitinates and degrades p73; WWP2 heterodimerizes with WWP1, and the WWP2/WWP1 heterodimer specifically ubiquitinates and degrades ΔNp73; phosphatase PPM1G acts as a functional switch controlling the balance between monomeric WWP2 and WWP2/WWP1 heterodimer, thereby differentially regulating p73 and ΔNp73 levels during cellular stress. Co-IP, ubiquitination assay, heterodimerization assay, PPM1G knockdown/overexpression Molecular and cellular biology High 25071155
2014 Wwp2 targets SRG3 (a scaffold protein of the BAF complex) for ubiquitination and proteasome-dependent degradation; interaction is mediated through the WW domain of Wwp2 and the PPPY motif of SRG3; catalytically inactive Wwp2 mutant abolishes SRG3 ubiquitination; Wwp2 and SRG3 co-localize in the nucleus. Co-IP, in vitro ubiquitination assay, active-site mutant, co-localization by immunofluorescence Biochemical and biophysical research communications Medium 24365151
2014 WWP2 interacts with Paip1 (poly(A)-binding protein-interacting protein 1) through its WW domain binding to the PAM2 motif (requiring two consecutive PXXY motifs), and promotes Paip1 ubiquitination and proteasomal degradation, thereby reducing translational stimulatory activity. Co-IP, domain-mapping, in vivo ubiquitination assay, translation reporter assay Molecular and cellular biology Medium 25266661
2015 Crystal structure of the HECT domain of human WWP2 was solved at 2.50 Å resolution; the overall structure displays an inverted T-shape with high conservation to Nedd4 subfamily members, providing the first structural template for WWP2 HECT domain. X-ray crystallography, molecular replacement Acta crystallographica. Section F, Structural biology communications High 26457515
2015 WWP2 binds ENaC subunits via three of its four WW domains in a PY motif-dependent manner and functionally inhibits ENaC-mediated Na+ transport when co-expressed in epithelia; mutation of ENaC PY motifs abolishes inhibition. WW-domain binding assays, co-expression in epithelial cells, electrophysiology, mutagenesis American journal of physiology. Renal physiology Medium 12167593
2015 WWP2 is autoinhibited by intramolecular interactions involving the WW domain 2,3-linker region; allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition; WW linker phosphorylation influences both catalytic activity and ubiquitin chain linkage type (K48 vs K63) and degree of polyubiquitination on substrates including PTEN, WBP2, and p62. In vitro ubiquitination assays with linker mutants and phosphomimics, SPR binding assays, mass spectrometry The Journal of biological chemistry High 31578285
2015 Dvl2 (Dishevelled) binds to WWP2 via its PPxY motif and unlocks WWP2 from autoinhibition; this disinhibition requires Dvl2 polymerization (signalosome formation) and partly requires the DEP domain; Dvl-activated WWP2 targets Notch intracellular domains for ubiquitination and degradation, providing a molecular mechanism for Wnt–Notch cross-talk; conserved in Drosophila where the WWP2 orthologue Su(dx) downregulates Notch upon activation by Dishevelled. Co-IP, ubiquitination assay, Dvl2 polymerization mutants, Drosophila genetic analysis Open biology High 26701932
2016 Cdh1 suppresses WWP2 E3 ligase activity in an APC/C-independent manner; loss of Cdh1 activates WWP2 leading to reduced PTEN levels and activation of PI3K/Akt oncogenic signaling. Co-IP, ubiquitination assay, Cdh1 KO/overexpression, PTEN immunoblotting Cell discovery Medium 27462441
2017 WWP2 mono-ubiquitinates RUNX2 in osteoblasts; this modification is catalyzed by WWP2 but does not lead to RUNX2 proteolysis; instead, mono-ubiquitination enhances RUNX2 transcriptional activity as shown by reporter assay; WWP2 ligase-dead mutant fails to augment RUNX2 activity; BMP receptor signaling promotes WWP2-dependent RUNX2 ubiquitination and transactivation; WWP2 knockdown in mesenchymal stem cells impairs osteogenesis. Co-IP, in vitro/in vivo ubiquitination assay, reporter assay, WWP2 KD in MSCs, ALP/mineralization assays The Journal of biological chemistry High 28500134
2018 WWP2 is required for proper axon-dendrite polarity in developing cortical neurons; double knockout of Wwp1 and Wwp2 causes defects in axon-dendrite polarity and aberrant laminar cortical distribution of pyramidal neurons; Sox9 induces transcription of the Wwp1 and Wwp2/miR-140 loci in neurons. Conditional KO mouse model, cortical neuron immunofluorescence, laminar distribution analysis Neuron Medium 30392800
2018 The E3 ligases Itch and WWP2 form a complex and cooperate to catalyze conjugation of atypical ubiquitin chains to the phosphatase SHP-1, reducing SHP-1 association with Lck and enhancing TCR-proximal signaling; mice lacking both Itch and WWP2 in T cells show spontaneous autoimmunity and CD4+ T cells biased toward TH2 differentiation. Co-IP, ubiquitination assay, Itch/WWP2 double KO mouse, T-cell differentiation assay, Lck-SHP-1 interaction assay Nature immunology High 29925997
2018 WWP2 is a physiological E3 ubiquitin ligase for PTEN in vivo; WWP2 knockout mice show elevated PTEN protein levels, reduced body size, and reduced AKT phosphorylation; CHIP knockout mice do not show elevated PTEN, and CHIP/WWP2 double KO phenotype mirrors WWP2 single KO, establishing WWP2 (not CHIP) as the relevant in vivo ligase. Conditional KO mouse models, PTEN/AKT immunoblotting, double KO epistasis The Journal of biological chemistry High 29685889
2019 WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII-transcribed genes; in response to DSBs, WWP2 targets RPB1 for K48-linked ubiquitylation, driving DNA-PK- and proteasome-dependent eviction of RNAPII; loss of WWP2 or expression of non-ubiquitylatable RPB1 abrogates binding of NHEJ factors (DNA-PK, XRCC4/DNA ligase IV) and impairs DSB repair. Co-IP, ChIP, K48-ubiquitylation assay, non-ubiquitylatable RPB1 mutant, NHEJ repair assay, WWP2 KO cells Genes & development High 31048545
2019 Wwp2 identifies Runx2 as a substrate; Wwp2 poly-ubiquitinates Runx2 for degradation; loss of Wwp2 E3 ligase activity (Wwp2-C838A knock-in mice) results in upregulation of Runx2-Adamts5 signaling in articular cartilage and aggravated osteoarthritis; intra-articular injection of Wwp2 mRNA reduces experimental OA severity. Wwp2 KO and Wwp2-C838A knock-in mice, Co-IP, ubiquitination assay, OA scoring, mRNA injection Nature communications High 31160553
2019 WWP2 (specifically the N-terminal isoform WWP2-N) regulates a pro-fibrotic gene network in the heart; TGFβ1 stimulation promotes nuclear translocation of N-terminal-containing WWP2 isoforms and their interaction with SMAD2; WWP2 mediates TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2; transgenic mice lacking the N-terminal region show reduced myocardial fibrosis and improved cardiac function. Transgenic mouse model, Co-IP, subcellular fractionation, SMAD2 transcriptional reporter, primary cardiac fibroblast assays Nature communications High 31399586
2019 NMR structure of the WWP2 WW4 domain was solved; WW4 binds a Smad7 PPxY-containing peptide; phosphorylation of Smad7 at S206 (adjacent to PPxY) enhances binding affinity for WW4; WW3 also binds Smad7 with enhanced affinity when expressed in tandem with WW4. NMR spectroscopy, SPR binding assay, phosphopeptide binding International journal of molecular sciences High 31546607
2019 WWP2 ligase activity is autoinhibited by the WW2,3-linker; tyrosine phosphorylation at Y369 in the 2,3-linker relieves autoinhibition; non-receptor tyrosine kinase ACK1 binds the WW3 domain of WWP2, phosphorylates WWP2 at the 2,3-linker, and partially activates ubiquitin ligase activity; EGF stimulates WWP2 tyrosine phosphorylation via ACK1. Co-IP, in vitro kinase assay, phosphomimetic mutant (Y369E), ubiquitination assay, EGF stimulation IUBMB life Medium 36773333
2020 WWP2 interacts with PARP1 (specifically its BRCT domain) via Co-IP, and mediates PARP1 ubiquitination and proteasome-dependent degradation; K418 and K249 of PARP1 are critical ubiquitination sites; cardiac-specific WWP2 knockout decreases PARP1 ubiquitination, increases PARP1/PARylation, and aggravates isoproterenol-induced cardiac hypertrophy, heart failure, and fibrosis. Cardiac-specific KO mouse, Co-IP, in vivo ubiquitination assay, PARP1 site-specific mutagenesis, cardiac phenotyping Cell death and differentiation High 32139900
2020 WWP2 promotes odontoblastic differentiation by monoubiquitinating the transcription factor KLF5 at K31, K52, K83, and K265; monoubiquitination is non-proteolytic and transactivates KLF5, promoting expression of odontoblast marker genes Dmp1 and Dspp; the PY2 motif of KLF5 and the C838 active site of WWP2 are required for this interaction and activity. Co-IP, in vitro/in vivo ubiquitination assay, active-site mutation (C838), PY motif mutagenesis, reporter assay, differentiation markers Journal of dental research High 33164644
2021 WWP2 is a bona fide E3 ubiquitin ligase for SOX2 in glioblastoma stem cells; TRIM26 stabilizes SOX2 by directly inhibiting SOX2 interaction with WWP2 via its PRYSPRY domain (independent of its own RING domain); competitive binding between TRIM26 and WWP2 controls SOX2 polyubiquitination and protein levels. Proteomic pulldown, Co-IP, ubiquitination assay, TRIM26/WWP2 competition assay, GSC functional assays Nature communications High 34732716
2021 WWP2 mediates GLI2 ubiquitination and degradation; DKK1 suppresses WWP2 expression through canonical Wnt/β-catenin signaling, leading to GLI2 stabilization and activation of Hedgehog pathway; WWP2 was identified as a direct target of Wnt/β-catenin signaling. Co-IP, ubiquitination assay, Wnt pathway reporter, WWP2 overexpression/KD Carcinogenesis Medium 34546340
2022 WWP2 interacts with IRF7 and promotes its non-degradative mono-ubiquitination, which facilitates IRF7 nuclear translocation and transcriptional activity, leading to upregulation of Ccl5; myeloid-specific deletion of WWP2 reduces Ccl5-expressing Ly6chigh monocyte infiltration and cardiac fibrosis in hypertension-induced cardiomyopathy. Co-IP, ubiquitination assay, myeloid-specific KO mouse, single-cell RNA-seq, nuclear fractionation Nature communications High 36450710
2022 WWP2 ubiquitinates autophagy receptors NDP52, OPTN, and SQSTM1; ubiquitination sites were mapped by mass spectrometry; WWP2 KO neuroblastoma cells show a defect in mitophagy that is rescued by WWP2-Y369E (activated) transfection; autoinhibition by the 2,3-linker modulates substrate ubiquitination; the activated phosphomimetic Y369E was used to identify 31 substrate hits on protein microarrays. Protein microarray, in vitro ubiquitination assay, mass spectrometry site-mapping, WWP2 KO by CRISPR-Cas9, mitophagy assay The Journal of biological chemistry High 35331737
2022 LAPTM5 triggers ubiquitin ligase WWP2 for lysosomal degradation upon BCR stimulation, resulting in accumulation of WWP2's substrate PTEN; elevated PTEN suppresses AKT phosphorylation, increasing FOXO1/p27/BIM to promote immature B cell apoptosis; LAPTM5 deficiency exacerbates autoantibody production in vivo. Co-IP, LAPTM5 KO/overexpression, PTEN/AKT/FOXO1 immunoblotting, B cell apoptosis assay, mouse autoimmunity model Proceedings of the National Academy of Sciences of the United States of America Medium 36037365
2023 WWP2 is an E3 ligase for Notch1 intracellular domain (NICD1), ubiquitinating it at K1821; lncRNA BREA2 impairs WWP2-NICD1 complex formation, thereby stabilizing NICD1 and activating Notch signaling to promote breast cancer metastasis. Co-IP, ubiquitination assay (K1821 site mapping), BREA2 gain/loss-of-function, Notch reporter, xenograft Proceedings of the National Academy of Sciences of the United States of America High 36795754
2023 WWP2 interacts with and promotes K63-linked polyubiquitination of DDX3X, targeting it for proteasomal degradation; WWP2 is downregulated in high glucose/palmitic acid-treated endothelial cells via JNK activation; endothelial-specific Wwp2 KO mice show aggravated T2DM-induced vascular endothelial injury. Mass spectrometry, Co-IP, ubiquitination linkage assay, pulse-chase, endothelial KO mouse, in vitro HG/PA model Cardiovascular diabetology Medium 37149668
2023 WWP2 interacts with LATS1 and promotes its ubiquitination and proteasome-dependent degradation, leading to increased YAP1 transcriptional activity; WWP2-mediated LATS1 degradation drives gastric cancer cell proliferation, migration, and invasion. Co-IP, cycloheximide chase, in vivo ubiquitination assay, WWP2 KD/OE, xenograft Cell communication and signaling : CCS Medium 36803368
2024 WWP2 promotes PARP1 ubiquitination and degradation in ALL cells; WWP2 KO enhances apoptosis induced by doxorubicin; WWP2 negatively regulates PARP1 protein levels through the polyubiquitin-proteasome pathway. Co-IP, ubiquitination assay, WWP2 KO, in vitro and in vivo apoptosis assay Cell death discovery Medium 36257929
2024 WWP2 suppresses the transcription of PGC-1α in renal myofibroblasts and controls mitochondrial respiration; WWP2 deficiency increases fatty acid oxidation and pentose phosphate pathway activity; WWP2 WWP2-PGC-1α axis regulates metabolic reprogramming that controls profibrotic activation. ChIP-seq, bulk RNA-seq, metabolomics, Seahorse metabolic flux assay, WWP2 KO mice Journal of the American Society of Nephrology : JASN Medium 38502123
2024 WWP2 mediates poly-ubiquitylation of CDC20, a negative regulator of autophagy; WWP2 deletion profoundly impairs autophagy in AKI kidneys; CDC20 selective inhibition protects against cisplatin-induced AKI, and rapamycin (autophagy activation) rescues WWP2 cKO mice; tubule-specific WWP2 KO aggravates renal dysfunction. Ubiquitylation omics, quantitative proteomics, Co-IP, tubule-specific KO mouse, rapamycin/3-MA pharmacology Journal of advanced research Medium 38909885
2025 WWP2 interacts with TFEB and directly induces TFEB ubiquitination but stabilizes TFEB protein (non-proteolytic); WWP2 is required for TFEB-dependent host defense response in human macrophages upon infection; the regulation is evolutionarily conserved (C. elegans WWP-1 regulates HLH-30/TFEB). Co-IP, ubiquitination assay, C. elegans genetic screen, WWP2 KD in human macrophages, infection assay iScience Medium 39995862
2025 NDFIP2 (canonical Ndfip) requires multiple PY motifs to interact with and activate WWP2; TMEM127 and SUSD6 function as a co-disinhibitory pair to activate WWP2; Salmonella effector SteD acts as a co-disinhibitory partner with TMEM127, interacting with WWP2 via its C2 domain rather than WW domains, to disinhibit WWP2. Co-IP, in vitro ubiquitination activity assay, domain-mapping, bacterial infection model The Journal of biological chemistry Medium 41135677
2025 α-arrestin ARRDC3 tyrosine Y394 phosphorylation functions as a phospho-regulatory switch: non-phosphorylated ARRDC3 binds WWP2 via its C-terminal PPxY motif; Y394 phosphorylation disrupts WWP2 interaction and perturbs ARRDC3-dependent lysosomal trafficking of protease-activated receptor-1. Co-IP, phospho-mutant analysis, lysosomal trafficking assay, receptor internalization The Journal of biological chemistry Medium 40409556
2025 WWP2 is shuttled to mitochondria during AKI-to-CKD transition where it ubiquitinates and degrades complex II subunit SDHC, impairing oxidative phosphorylation; tubular-specific Wwp2 depletion ameliorates OXPHOS dysfunction; SDHC knockdown abolishes protection from Wwp2 deletion; two candidate WWP2 inhibitors identified by virtual screening improve TEC repair. Mitochondrial fractionation, ubiquitination assay, tubule-specific KO, SDHC rescue experiment, virtual screening + enzyme activity assay Molecular therapy : the journal of the American Society of Gene Therapy Medium 41254942
2025 WWP2 promotes K48-linked ubiquitination and proteasomal degradation of p21 (CDKN1A) in hepatocellular carcinoma; CMTM6 directly interacts with WWP2, stabilizing p21 by preventing WWP2-mediated ubiquitination; the WWP2-CMTM6-p21 axis regulates cellular senescence and HCC progression. Co-IP, ubiquitination assay (K48-linked), WWP2 KD/CMTM6 KD, cellular senescence assay, xenograft Cell death & disease Medium 41387673
2025 WWP2 targets MAVS for ubiquitination and degradation, preventing MAVS-mediated mitochondrial translocation of NLRP3; WWP2 overexpression in microglia inhibits NLRP3 inflammasome activation and alleviates MCAO/reperfusion injury; nuclear export of TDP-43 promotes WWP2 mRNA instability via the (UG)n element of WWP2 3'UTR. Co-IP, ubiquitination assay, MAVS/NLRP3 interaction assay, WWP2 OE in microglia, MCAO mouse model Glia Medium 40781638
2026 WWP2 promotes K48-linked ubiquitination of BAK at K113, targeting BAK for proteasomal degradation; oxidative stress weakens WWP2-BAK interaction and reduces WWP2 expression, increasing BAK protein and mitochondrial apoptosis in granulosa cells; Wwp2 KO in PCOS mice aggravates granulosa cell apoptosis and hormonal disturbances. Co-IP, ubiquitination assay (K113 site-specific mutant), Wwp2 KO PCOS mouse model, apoptosis assay Cell death & disease Medium 41730845
2020 WWP2 interacts with BRCC3 (BRCC36) and mediates its ubiquitination and proteasome-dependent degradation; ABRO1 (a BRISC subunit) competes with WWP2 to bind BRCC3, preventing WWP2-mediated BRCC3 ubiquitination and enhancing BRCC3 stability; WWP2 overexpression in macrophages inhibits NLRP3 inflammasome activation by decreasing BRCC3 levels. Co-IP, ubiquitination assay, competition binding assay, lentiviral overexpression, NLRP3 activation assay FEBS letters Medium 33107021
2020 WWP2 interacts with SIRT1 and STAT3, forming a ternary complex that reduces SIRT1-STAT3 interaction, thereby promoting STAT3-K685 acetylation and STAT3-Y705 phosphorylation in VSMCs; WWP2 promotes VSMC proliferation, migration, and phenotypic transformation; vascular smooth muscle-specific WWP2 KO mice show reduced angiotensin II-induced hypertensive angiopathy. Mass spectrometry, Co-IP, VSMC-specific KO mouse, STAT3 acetylation/phosphorylation assays Journal of cellular and molecular medicine Medium 32627301
2024 WWP2 ubiquitinates ATP5A (ATP synthase α subunit) and targets it for proteasomal degradation, stabilizing Bcl-2/Bax balance in the mitochondrial apoptosis pathway; atorvastatin upregulates WWP2 to counteract angiotensin II-induced vascular endothelial injury; endothelial-specific WWP2 KO abrogates atorvastatin's protective effects. Co-IP, ubiquitination assay, endothelial-specific KO mouse, atorvastatin treatment, apoptosis assay Biomedicine & pharmacotherapy Medium 37557013
2025 MEF2A transcriptionally activates WWP2 expression; WWP2 promotes ubiquitination and degradation of SH2B3 (LNK); this MEF2A-WWP2-SH2B3 axis changes microglial activation status and ameliorates BMEC injury in ischemic stroke. Dual-luciferase reporter, ChIP assay, Co-IP, ubiquitination assay, MCAO mouse model Neurochemical research Medium 40407948
2024 PHF8 epigenetically regulates WWP2 expression by demethylating H3K9me2 at the WWP2 promoter; WWP2 interacts with and promotes ubiquitination-dependent degradation of CXCR4; the PHF8-WWP2-CXCR4 axis protects against fluid shear stress-induced chondrocyte injury and posttraumatic OA. ChIP assay (H3K9me2), Co-IP, ubiquitination assay, ACLT mouse model, rescue experiments Human & experimental toxicology Medium 39454680
2024 WWP2 interacts with LATS2 and promotes its ubiquitination and degradation; CMTM5 decreases WWP2 expression and thereby reduces LATS2 ubiquitination, enhancing LATS2 expression and YAP1 phosphorylation to promote ferroptosis in glioma. Co-IP, ubiquitination assay, CMTM5 overexpression, xenograft model The Kaohsiung journal of medical sciences Medium 39166861
2025 WWP2 directly interacts with and promotes ubiquitin-mediated proteasomal degradation of p53 in colorectal cancer; WWP2 overexpression reduces p53 and p21 levels, promotes CRC cell proliferation, migration, and invasion, and enhances tumor growth in xenograft mice. Co-IP, ubiquitination assay, WWP2 overexpression, xenograft Annals of surgical treatment and research Medium 42131422
2025 WWP2 binds NKRF (NF-κB-repressing factor) via Co-IP and promotes NKRF ubiquitylation; this interaction activates NF-κB signaling and promotes AML cell proliferation; NKRF overexpression abolishes WWP2-mediated AML progression. Co-IP, ubiquitination assay, lentiviral WWP2 OE/KD, NKRF rescue experiment Biochemistry and cell biology Medium 37921219
2024 WWP2 interacts with FACL4 (ACSL4, acyl-CoA synthetase long-chain family member 4) via Co-IP and facilitates its ubiquitin-dependent degradation; cardiac-specific WWP2 overexpression suppresses LPS-induced cardiomyocyte ferroptosis; WWP2 KO aggravates sepsis-induced cardiac injury and is rescued by FACL4 knockdown. Co-IP, ubiquitination assay, cardiac-specific OE/KO, FACL4 rescue, ferroptosis markers Journal of translational internal medicine Medium 38591063
2022 WWP2 interacts with PDCD4 (programmed cell death 4) via Co-IP; WWP2 overexpression increases PDCD4 ubiquitination under proteasome inhibition; WWP2 promotes PDCD4 degradation and thereby protects against ox-LDL-induced endothelial injury via the PDCD4/HO-1 pathway. Co-IP, ubiquitination assay, WWP2 OE/KD, HO-1 pathway rescue Acta biochimica et biophysica Sinica Medium 35983977
2022 WWP2 promotes WWP2-FL isoform expression through CPSF7-mediated alternative mRNA processing; WWP2-FL contains PTEN ubiquitination sites absent in shorter isoforms; CPSF7 knockdown suppresses PTEN/AKT signaling in liver cancer through reduced WWP2-FL. Alternative splicing analysis, WWP2-FL isoform expression, PTEN ubiquitination assay, CPSF7 KD Biochimica et biophysica acta. Molecular cell research Low 31837982
2020 WWP2 interacts with p53 via Co-IP and regulates its ubiquitylation and degradation through the proteasome pathway in acute kidney injury cells; WWP2 overexpression promotes HK-2 cell proliferation and inhibits apoptosis after ischemia-reperfusion injury; effects are blocked by the proteasome inhibitor MG132. Co-IP, immunoprecipitation ubiquitination assay, WWP2 OE, MG132 rescue, cell proliferation/apoptosis Cell biochemistry and function Low 32248569

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The AIP2 E3 ligase acts as a novel negative regulator of ABA signaling by promoting ABI3 degradation. Genes & development 308 15998807
2011 WWP2 is an E3 ubiquitin ligase for PTEN. Nature cell biology 266 21532586
2011 Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nature communications 125 21427722
2004 Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. The Journal of biological chemistry 124 15047715
2008 Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 119 18776082
2020 Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling. Cell death and differentiation 113 32139900
2011 Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. The EMBO journal 113 21847096
2009 WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells. Cell research 112 19274063
2011 MiR-140 is co-expressed with Wwp2-C transcript and activated by Sox9 to target Sp1 in maintaining the chondrocyte proliferation. FEBS letters 109 21872590
2013 E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America 99 23479606
2010 The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid. Nature cell biology 92 21170031
2019 Wwp2 maintains cartilage homeostasis through regulation of Adamts5. Nature communications 91 31160553
2019 WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks. Genes & development 83 31048545
2009 Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner. Cell research 83 19997087
2011 Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT. Oncogene 73 21258410
2007 Wwp2-mediated ubiquitination of the RNA polymerase II large subunit in mouse embryonic pluripotent stem cells. Molecular and cellular biology 65 17526739
2023 lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1. Proceedings of the National Academy of Sciences of the United States of America 59 36795754
2019 WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature communications 59 31399586
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
2012 MiR-25 regulates Wwp2 and Fbxw7 and promotes reprogramming of mouse fibroblast cells to iPSCs. PloS one 57 22912667
2002 Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel. American journal of physiology. Renal physiology 57 12167593
2021 Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma. Nature communications 52 34732716
2009 The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination. Molecular and cellular biology 49 19651900
2017 The E3 ubiquitin ligase WWP2 facilitates RUNX2 protein transactivation in a mono-ubiquitination manner during osteogenic differentiation. The Journal of biological chemistry 48 28500134
2018 The E3 ligases Itch and WWP2 cooperate to limit TH2 differentiation by enhancing signaling through the TCR. Nature immunology 40 29925997
2016 Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner. Cell discovery 40 27462441
2015 Disinhibition of the HECT E3 ubiquitin ligase WWP2 by polymerized Dishevelled. Open biology 40 26701932
2022 The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis. Nature communications 39 36450710
2020 ARHGAP24 inhibits cell proliferation and cell cycle progression and induces apoptosis of lung cancer via a STAT6-WWP2-p27 axis. Carcinogenesis 37 31430374
2014 WWP2-WWP1 ubiquitin ligase complex coordinated by PPM1G maintains the balance between cellular p73 and ΔNp73 levels. Molecular and cellular biology 33 25071155
2018 WWP2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (PTEN) in mice. The Journal of biological chemistry 32 29685889
2014 WWP2: a multifunctional ubiquitin ligase gene. Pathology oncology research : POR 32 25216927
2019 Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases. The Journal of biological chemistry 31 31578285
2024 WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts. Journal of the American Society of Nephrology : JASN 30 38502123
2019 Dysregulated expressions of PTEN, NF-κB, WWP2, p53 and c-Myc in different subtypes of B cell lymphoma and reactive follicular hyperplasia. American journal of translational research 30 30899409
2018 WWP2 Is One Promising Novel Oncogene. Pathology oncology research : POR 30 30415470
2022 LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway. Proceedings of the National Academy of Sciences of the United States of America 29 36037365
2019 CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway. Biochimica et biophysica acta. Molecular cell research 27 31837982
2023 WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein. Cell communication and signaling : CCS 26 36803368
2023 Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X. Cardiovascular diabetology 26 37149668
2011 WWP2 ubiquitin ligase and its isoforms: new biological insight and promising disease targets. Cell cycle (Georgetown, Tex.) 26 21750408
2016 Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells. Oncotarget 23 26894970
2016 Inhibition of WWP2 suppresses proliferation, and induces G1 cell cycle arrest and apoptosis in liver cancer cells. Molecular medicine reports 22 26783238
2019 WWP2 regulates proliferation of gastric cancer cells in a PTEN-dependent manner. Biochemical and biophysical research communications 21 31677789
2015 WWP2 and its association with PTEN in endometrial cancer. Gynecologic oncology reports 21 26425715
2024 WWP2 protects against sepsis-induced cardiac injury through inhibiting cardiomyocyte ferroptosis. Journal of translational internal medicine 20 38591063
2020 WWP2 Promotes Odontoblastic Differentiation by Monoubiquitinating KLF5. Journal of dental research 20 33164644
2016 Elevated expression of WWP2 in human lung adenocarcinoma and its effect on migration and invasion. Biochemical and biophysical research communications 20 27462019
2020 WWP2 regulates SIRT1-STAT3 acetylation and phosphorylation involved in hypertensive angiopathy. Journal of cellular and molecular medicine 19 32627301
2015 Structure of the HECT domain of human WWP2. Acta crystallographica. Section F, Structural biology communications 19 26457515
2022 WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma. Cell biology international 18 35880837
2020 ABRO1 stabilizes the deubiquitinase BRCC3 through inhibiting its degradation mediated by the E3 ubiquitin ligase WWP2. FEBS letters 18 33107021
2016 Silencing of hypoxia-inducible factor-1α promotes thyroid cancer cell apoptosis and inhibits invasion by downregulating WWP2, WWP9, VEGF and VEGFR2. Experimental and therapeutic medicine 18 28105105
2014 Paip1, an effective stimulator of translation initiation, is targeted by WWP2 for ubiquitination and degradation. Molecular and cellular biology 17 25266661
2021 Etomidate inhibits cell proliferation and induces apoptosis in A549 non-small cell lung cancer cells via downregulating WWP2. Experimental and therapeutic medicine 16 34603522
2021 DKK1 suppresses WWP2 to enhance bortezomib resistance in multiple myeloma via regulating GLI2 ubiquitination. Carcinogenesis 15 34546340
2022 Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates. The Journal of biological chemistry 14 35331737
2022 RNAi and CRISPR-Cas silencing E3-RING ubiquitin ligase AIP2 enhances soybean seed protein content. Journal of experimental botany 14 36112496
2015 Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 14 26662306
2022 A WWP2-PTEN-KLF5 signaling axis regulates odontoblast differentiation and dentinogenesis in mice. The Journal of biological chemistry 13 35780838
2022 WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway. Acta biochimica et biophysica Sinica 13 35983977
2022 LINC01588 regulates WWP2-mediated cardiomyocyte injury by interacting with HNRNPL. Environmental toxicology 11 35258167
2022 miR-328-5p Induces Human Intervertebral Disc Degeneration by Targeting WWP2. Oxidative medicine and cellular longevity 11 36211818
2020 WWP2 ameliorates acute kidney injury by mediating p53 ubiquitylation and degradation. Cell biochemistry and function 11 32248569
2015 WWP2 is required for normal cell cycle progression. Genes & cancer 11 26622940
2024 E3 ubiquitin ligase WWP2 as a promising therapeutic target for diverse human diseases. Molecular aspects of medicine 9 38430667
2022 The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia. Cell death discovery 9 36257929
2019 Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms. International journal of molecular sciences 9 31546607
2018 MicroRNA‑32 silences WWP2 expression to maintain the pluripotency of human amniotic epithelial stem cells and β islet‑like cell differentiation. International journal of molecular medicine 9 29393344
2013 Wwp2 targets SRG3, a scaffold protein of the SWI/SNF-like BAF complex, for ubiquitination and degradation. Biochemical and biophysical research communications 9 24365151
2024 The role of WWP1 and WWP2 in bone/cartilage development and diseases. Molecular and cellular biochemistry 8 38252355
2024 WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis. Journal of advanced research 8 38909885
2023 Atorvastatin rescues vascular endothelial injury in hypertension by WWP2-mediated ubiquitination and degradation of ATP5A. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 37557013
2024 Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence. Arthritis research & therapy 7 38570801
2024 CMTM5 influences Hippo/YAP axis to promote ferroptosis in glioma through regulating WWP2-mediated LATS2 ubiquitination. The Kaohsiung journal of medical sciences 7 39166861
2022 WWP2 confers risk to osteoarthritis by affecting cartilage matrix deposition via hypoxia associated genes. Osteoarthritis and cartilage 7 36208715
2024 Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3. PloS one 6 38166045
2015 Characterization of substrate binding of the WW domains in human WWP2 protein. FEBS letters 6 25999310
2025 Sculponeatin A induces mitochondrial dysfunction in non-small cell lung cancer through WWP2-mediated degradation of mitochondrial STAT3. British journal of pharmacology 5 39993792
2023 Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1. IUBMB life 5 36773333
2014 Expression and purification of human WWP2 HECT domain in Escherichia coli. Protein expression and purification 4 25554193
2025 The Ubiquitination and Degradation of SH2B3 Mediated by MEF2A/WWP2 Axis Restores Microglial Homeostasis to Alleviate Cerebral Microvascular Endothelial Cell Injury in Ischemic Stroke. Neurochemical research 3 40407948
2025 DEF6 regulates renal ischemia reperfusion injury through suppressing the WWP2 mediated ubiquitination of PARP1. Biochimica et biophysica acta. Molecular basis of disease 2 39837430
2025 Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo. iScience 2 39995862
2025 circGIGYF1 inhibits stemness and metastasis in colorectal cancer by promoting WWP2-HOXD13 interaction to regulate β-catenin signalling. Communications biology 2 40595410
2024 Histone demethylase PHF8 protected against chondrocyte injury and alleviated posttraumatic osteoarthritis by epigenetically enhancing WWP2 expression. Human & experimental toxicology 2 39454680
2023 Apigenin promotes cell death in NCI-H23 cells by upregulation of PTEN: potential involvement of the binding of apigenin with WWP2 protein. Journal of biomolecular structure & dynamics 2 37870050
2022 Hypoxia-induced mesenchymal stem cells inhibit corneal fibroblast proliferation by regulating the WWP2/Notch1 axis. Regenerative medicine 2 35545948
2021 WWP2 and PPP1R3A are abnormally regulated in arrhythmia-induced cardiac damage. 3 Biotech 2 33927976
2025 Targeting renal tubular WWP2 to restore mitochondrial OXPHOS integrity retards the AKI-to-CKD transition. Molecular therapy : the journal of the American Society of Gene Therapy 1 41254942
2025 FAM189A2 activates Hippo signaling pathway by abrogating WWP2-mediated LATS1 ubiquitination, to inhibit the glycolysis and proliferation processes of lung adenocarcinoma. Journal of translational medicine 1 41350729
2023 WWP2 binds to NKRF, enhances the NF-κB signaling, and promotes malignant phenotypes of acute myeloid leukemia cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 1 37921219
2020 [The association study of WWP2 gene polymorphisms with delayed encephalopathy after acute carbon monoxide poisoning]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 1 32746566
2026 The E3 ligases Itch and WWP2 regulate autoimmune neuroinflammation by controlling TH2 to TH17 cell conversion via interleukin-4-STAT5 axis in mice. Nature communications 0 41577662
2026 WWP2 underlies ROS-induced granulosa cell apoptosis by promoting ubiquitination of BAK in polycystic ovary syndrome. Cell death & disease 0 41730845
2026 WWP2 ubiquitin ligase promotes colorectal cancer progression by targeting p53 for degradation: an experimental study. Annals of surgical treatment and research 0 42131422
2025 ARRDC3 tyrosine phosphorylation functions as a switch to control c-Src versus WWP2 interactions and distinct scaffolding functions. The Journal of biological chemistry 0 40409556
2025 WWP2 Overexpression Represses NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Injury Through the Degradation of MAVS. Glia 0 40781638
2025 Mammalian and bacterial adaptors function as co-disinhibitory pairs to activate the E3 ubiquitin ligase WWP2. The Journal of biological chemistry 0 41135677
2025 WWP2-induced inhibition of hepatocellular carcinoma cellular senescence via the ubiquitination and degradation of p21. Cell death & disease 0 41387673

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