Affinage

WWP2

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

Length
870 aa
Mass
98.9 kDa
Annotated
2026-04-28
100 papers in source corpus 55 papers cited in narrative 55 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WWP2 is a NEDD4-family HECT-type E3 ubiquitin ligase that governs diverse cellular processes—including TGF-β/Notch/Hippo signaling, innate and adaptive immunity, DNA damage repair, autophagy, and stem cell differentiation—by ubiquitinating a broad substrate repertoire through its WW domains, which recognize PPxY motifs on substrates or adaptor proteins. WWP2 exists in an autoinhibited conformation maintained by WW-domain linker regions (particularly the 2,3-linker); relief of autoinhibition is achieved by adaptor proteins (Ndfip1/2, TMEM127/SUSD6), Dishevelled polymerization, ACK1-mediated tyrosine phosphorylation, or heterodimerization with its own N-terminal isoform (WWP2-N), enabling catalysis of K48-linked polyubiquitination (driving proteasomal degradation of PTEN, TRIF, Smad7, PARP1, RPB1, LATS1, and others) or mono-/K63-linked ubiquitination (activating transcription factors Goosecoid, RUNX2, KLF5, and IRF7) (PMID:25071155, PMID:31578285, PMID:26701932, PMID:41135677, PMID:21258410, PMID:31048545, PMID:36450710, PMID:21532586). Tissue-specific and global knockout models demonstrate non-redundant physiological roles: WWP2 loss causes craniofacial malformations, elevated PTEN with reduced AKT signaling, exaggerated TLR3-driven inflammation, cardiac fibrosis and hypertrophy, impaired NHEJ repair, defective neuronal polarity, and dysregulated T cell signaling (PMID:21170031, PMID:29685889, PMID:23479606, PMID:31399586, PMID:31048545, PMID:30392800, PMID:29925997). Multiple isoforms (WWP2-FL, WWP2-N, WWP2-C) exhibit distinct substrate selectivities—WWP2-N lacks the HECT domain yet activates WWP2-FL toward Smad2/3 in a TGF-β-regulated manner, and the WWP2-N-containing isoforms drive cardiac fibrosis through SMAD2 nuclear shuttling (PMID:21258410, PMID:31399586).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    Establishing that WWP2 directly regulates ion channel activity via PPxY-motif-dependent interactions resolved how NEDD4-family ligases extend beyond proteolytic targeting to modulate membrane transporter function.

    Evidence WW domain binding assays and electrophysiology with ENaC PY-motif mutants in epithelial cells

    PMID:12167593

    Open questions at the time
    • Whether WWP2 ubiquitinates ENaC directly or acts through adaptor-mediated recruitment was not determined
    • In vivo relevance to epithelial sodium handling not tested
  2. 2004 High

    Identifying Oct-4 as the first transcription factor substrate of WWP2 revealed that this ligase controls pluripotency factor turnover in embryonic stem cells, establishing WWP2 as a regulator of stem cell biology.

    Evidence In vitro ubiquitination, active-site mutagenesis, and reporter assays in mouse ES cells; confirmed in human ES cells with proteasome inhibitors and RNAi

    PMID:15047715 PMID:19274063 PMID:19997087

    Open questions at the time
    • Whether Oct4 ubiquitination by WWP2 is the rate-limiting step in differentiation-coupled Oct4 loss in vivo
  3. 2007 High

    Discovery that WWP2 ubiquitinates the RNAPII large subunit RPB1 at CTD lysines—independent of DNA damage—opened the question of how WWP2 participates in transcription-coupled processes beyond substrate degradation.

    Evidence Co-IP, in vitro ubiquitination with domain mapping, RNAi knockdown elevating RPB1 levels

    PMID:17526739

    Open questions at the time
    • Physiological context triggering RPB1 ubiquitination was unclear until the 2019 DSB repair study
  4. 2008 High

    Demonstration that Ndfip1/2 adaptors bridge WWP2 to substrates lacking PPxY motifs (DMT1) established the adaptor-dependent recruitment paradigm for NEDD4-family ligases.

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

    PMID:18776082

    Open questions at the time
    • Full spectrum of Ndfip-dependent WWP2 substrates not catalogued
  5. 2010 High

    Showing that WWP2 mono-ubiquitinates Goosecoid to activate (not degrade) it, with Wwp2-KO mice developing craniofacial malformations, established that WWP2 catalyzes non-proteolytic ubiquitination with developmental consequences in vivo.

    Evidence Mono-ubiquitylation assay, reporter assays, Wwp2-KO mouse craniofacial phenotype

    PMID:21170031

    Open questions at the time
    • Structural basis for how WWP2 selects mono- versus poly-ubiquitination on different substrates
  6. 2011 High

    Mapping isoform-specific Smad substrate selectivity (WWP2-FL/N/C targeting different Smads) and showing that the HECT-less WWP2-N isoform allosterically activates WWP2-FL revealed an intra-gene regulatory mechanism governing TGF-β pathway output.

    Evidence Co-IP, ubiquitination assay, isoform overexpression/knockdown, EMT reporter assay

    PMID:21258410

    Open questions at the time
    • How TGF-β signal regulates WWP2-N/FL dimerization stoichiometry in vivo
    • Whether WWP2-N activates other NEDD4-family ligases
  7. 2011 High

    Concurrent identification of PTEN, ADAR2, and Sox9/Med25 as WWP2 substrates or partners expanded the ligase's substrate portfolio to tumor suppression, RNA editing, and chondrogenic transcription.

    Evidence Tandem affinity purification (PTEN), Co-IP/ubiquitination (ADAR2), yeast two-hybrid plus zebrafish morpholino (Sox9/Med25)

    PMID:21427722 PMID:21532586 PMID:21847096

    Open questions at the time
    • How substrate competition is resolved when multiple substrates share WW-domain binding
  8. 2013 High

    Identifying TRIF as a K48-linked ubiquitination substrate with Wwp2-KO mice showing exaggerated TLR3-driven cytokine responses established WWP2 as a negative regulator of innate antiviral immunity.

    Evidence Biochemical purification, K48-linkage-specific assay, Wwp2-KO mouse innate immune phenotype

    PMID:23479606

    Open questions at the time
    • Whether WWP2 regulates other TLR adaptor proteins
    • Contribution of WWP2 to antiviral defense in natural infection
  9. 2014 High

    Discovery that WWP2 forms a heterodimer with WWP1 under PPM1G control to switch substrate specificity from p73 to ΔNp73 revealed a phosphatase-gated complex-composition switch determining pro- vs anti-apoptotic output.

    Evidence Co-IP, ubiquitination assay, phosphatase functional experiments, knockdown

    PMID:25071155

    Open questions at the time
    • Whether other phosphatases can substitute for PPM1G
    • Structural basis of the WWP1–WWP2 heterodimer
  10. 2015 High

    Solving the crystal structure of the WWP2 HECT domain and demonstrating that Dishevelled polymerization relieves WW-domain-mediated autoinhibition to enable Notch ICD ubiquitination provided the first structural and mechanistic framework for WWP2 activation.

    Evidence X-ray crystallography at 2.5 Å; Co-IP and ubiquitination with Dvl2 polymerization mutants and Drosophila Su(dx) genetics

    PMID:26457515 PMID:26701932

    Open questions at the time
    • Full-length WWP2 structure with autoinhibitory linker not yet solved
    • Quantitative activation kinetics
  11. 2018 High

    Genetic demonstration that Itch and WWP2 cooperate to ubiquitinate SHP-1 with atypical chains, controlling TCR-proximal signaling—with double-KO mice developing spontaneous autoimmunity—defined WWP2's non-redundant role in adaptive immune homeostasis.

    Evidence Itch/WWP2 double-KO mouse, ubiquitination assay, T cell functional assays

    PMID:29925997

    Open questions at the time
    • Identity of the specific atypical ubiquitin chain type on SHP-1
    • Whether WWP2 cooperates with Itch on other immune substrates
  12. 2018 High

    Wwp1/Wwp2 double-KO disrupted axon-dendrite polarity in cortical neurons, linking WWP2 to neuronal development and revealing that the miR-140 encoded within the Wwp2 intron contributes to polarity via Fyn kinase repression.

    Evidence Wwp1/Wwp2 double-KO mouse, neuronal morphology analysis, miR-140 functional assays

    PMID:30392800

    Open questions at the time
    • Direct neuronal ubiquitination substrates of WWP2 not identified
    • Relative contributions of WWP2 ligase activity versus miR-140
  13. 2019 High

    Consolidating WWP2's physiological roles through multiple tissue-specific KO models: WWP2-KO elevated PTEN/reduced AKT in vivo (dominant over CHIP); WWP2-N-deletion reduced cardiac fibrosis via SMAD2; RPB1 K48-ubiquitination by WWP2 at DSBs enabled RNAPII eviction for NHEJ; and linker-region autoinhibition was biochemically dissected.

    Evidence WWP2-KO and CHIP/WWP2 double-KO mice; cardiac transgenic mice; ChIP and NHEJ repair assays; in vitro linker-mutant ubiquitination reconstitution; NMR of WW4-Smad7 complex

    PMID:29685889 PMID:31048545 PMID:31399586 PMID:31546607 PMID:31578285

    Open questions at the time
    • Full structural view of autoinhibited WWP2 with all four WW domains and linkers
    • Whether RPB1 ubiquitination by WWP2 also functions in transcription-coupled nucleotide excision repair
  14. 2020 High

    Identifying PARP1 as a cardiac WWP2 substrate (ubiquitinated at K418/K249), with cardiac-specific KO aggravating hypertrophy through increased PARylation, established WWP2 as a cardioprotective factor via PARP1 turnover control.

    Evidence Cardiac-specific WWP2-KO, ubiquitination site mapping, H9c2 knockdown/re-expression

    PMID:32139900

    Open questions at the time
    • Whether PARP1 ubiquitination by WWP2 also modulates DNA repair in non-cardiac contexts
    • Contribution relative to other PARP1 E3 ligases (e.g., RNF146)
  15. 2022 High

    Non-degradative mono-ubiquitination of IRF7 by WWP2 driving its nuclear translocation and Ccl5 transcription in monocytes, along with K48-ubiquitination of autophagy receptors NDP52/OPTN/SQSTM1 and LATS1, expanded the functional output of WWP2 to innate immune gene activation, mitophagy regulation, and Hippo pathway control.

    Evidence Mono-ubiquitination assay with myeloid-specific KO; protein microarray with phosphomimetic WWP2Y369E; CRISPR-KO mitophagy assay; LATS1 co-IP and xenograft

    PMID:35331737 PMID:36450710 PMID:36803368

    Open questions at the time
    • Whether LATS1 ubiquitination is K48-linked specifically
    • How WWP2 distinguishes mono- from poly-ubiquitination of IRF7 versus degradative substrates
    • In vivo validation of autophagy receptor regulation
  16. 2023 Medium

    Identification of ACK1 as a tyrosine kinase that phosphorylates the WWP2 2,3-linker to relieve autoinhibition downstream of EGF signaling provided a receptor-linked activation mechanism for WWP2.

    Evidence In vitro kinase assay, phosphomimetic mutants, WWP2 knockdown in A549 cells

    PMID:36773333

    Open questions at the time
    • Exact phosphorylation sites on the 2,3-linker not fully mapped
    • Whether other RTK-activated kinases similarly regulate WWP2
    • Not independently confirmed
  17. 2025 High

    Elucidation of a co-disinhibitory activation mechanism—where single-PY-motif proteins (TMEM127 + SUSD6, or TMEM127 + Salmonella SteD) pair to activate WWP2—revealed how pathogens hijack WWP2 regulation and broadened the activation paradigm beyond multi-PY adaptors like Ndfip2.

    Evidence In vitro ubiquitination reconstitution, PY motif and C2 domain mutagenesis

    PMID:41135677

    Open questions at the time
    • Structural basis of the co-disinhibitory pair binding geometry
    • Physiological substrates targeted during Salmonella infection via SteD-TMEM127-WWP2
  18. 2025 High

    Discovery that WWP2 ubiquitinates mitochondrial SDHC (complex II) during kidney injury, and CDC20 to promote autophagy, with tubular-specific KO validating both pathways, extended WWP2 function to mitochondrial metabolism and autophagy in renal pathophysiology.

    Evidence Tubular-specific Wwp2-KO mice, ubiquitylation omics, SDHC/CDC20 knockdown rescue, OXPHOS assay

    PMID:38909885 PMID:41254942

    Open questions at the time
    • Whether SDHC ubiquitination occurs under physiological conditions or only pathological stress
    • Selectivity mechanism for WWP2 mitochondrial targeting

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the full-length autoinhibited structure of WWP2 with all WW domains and linkers; (2) the combinatorial logic by which WWP2 selects mono- versus K48- versus K63-linked ubiquitination on different substrates; (3) how substrate competition is resolved in cells where dozens of PPxY-containing substrates coexist; and (4) whether WWP2 loss-of-function mutations cause a defined human Mendelian disorder.
  • No full-length structure
  • Ubiquitin chain-type selectivity mechanism unknown
  • No human genetic disease firmly established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 30 GO:0016874 ligase activity 4
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 11 R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
DVL2ITCHNDFIP1NDFIP2PARP1PTENSMAD7WWP1
Complex memberships
Itch-WWP2 heterodimerWWP1-WWP2 heterodimerWWP2-FL/WWP2-N dimer

Evidence

Reading pass · 55 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 WWP2 (mouse Wwp2) is an E3 ubiquitin ligase that specifically interacts with the POU transcription factor Oct-4 via its WW domain and promotes Oct-4 ubiquitination both in vivo and in vitro; a catalytically inactive point mutant abolishes this ubiquitination; overexpression of WWP2 in embryonic stem cells reduces Oct-4 transcriptional activity, and fusion of a single ubiquitin to Oct-4 inactivates its transcriptional activity. In vitro ubiquitination assay, co-immunoprecipitation, active-site mutagenesis, reporter assay in ES cells The Journal of biological chemistry High 15047715
2007 Mouse Wwp2 interacts with the large subunit of RNA polymerase II (Rpb1) through its WW domain binding to the CTD of Rpb1, and targets Rpb1 for ubiquitination both in vitro and in vivo at six lysine residues in the CTD; this interaction and ubiquitination are independent of Rpb1 phosphorylation state and DNA damage; knockdown of Wwp2 elevates steady-state Rpb1 protein levels. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown, domain mapping Molecular and cellular biology High 17526739
2008 WWP2 mediates ubiquitination and degradation of the divalent metal ion transporter DMT1; DMT1 lacks a direct WW-binding motif but interacts with adaptor proteins Ndfip1 and Ndfip2, which bridge the interaction with WWP2 and promote DMT1 ubiquitination; Ndfip1-knockout mice show increased DMT1 activity and hepatic iron deposition. Co-immunoprecipitation, ubiquitination assay, Ndfip1 knockout mouse model Blood High 18776082
2009 Human WWP2 promotes degradation of OCT4 through the 26S proteasome in a dosage-dependent manner via its WW domain interaction with OCT4; the active-site cysteine of WWP2 is required for both enzymatic activity and proteolytic effect; RNAi knockdown of WWP2 in human ES cells significantly elevates endogenous OCT4 protein levels. Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, RNAi knockdown, proteasome inhibitor treatment Cell research High 19274063
2009 Mouse Wwp2 catalyzes Oct4 poly-ubiquitination via K63 linkage in a dosage-dependent manner during differentiation of embryonal carcinoma cells; Wwp2 also undergoes auto-ubiquitination through an intramolecular mechanism; inhibition of Wwp2 by RNAi elevates endogenous Oct4 protein and attenuates retinoic acid-induced differentiation. In vitro ubiquitination assay, linkage-specific analysis, RNAi knockdown, intramolecular auto-ubiquitination assay Cell research High 19997087
2009 The HECT-type E3 ligase AIP2/WWP2 interacts with EGR2 and catalyzes its ubiquitin-mediated degradation; overexpression of AIP2 in mouse primary T cells enhances proliferation and IL-2 production by suppressing EGR2-mediated FasL expression; RNAi knockdown of AIP2 upregulates EGR2 and enhances T cell apoptosis. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown, primary T cell functional assay Molecular and cellular biology High 19651900
2010 WWP2 interacts with the paired-like homeobox transcription factor Goosecoid (Gsc) and facilitates its mono-ubiquitylation, a non-proteolytic modification required for optimal Gsc transcriptional activation of Sox6; Wwp2-deficient mice develop craniofacial malformations; Sox9 controls Wwp2 expression in cartilage. Co-immunoprecipitation, mono-ubiquitylation assay, Wwp2 knockout mouse, reporter assay Nature cell biology High 21170031
2011 WWP2 is an E3 ubiquitin ligase for PTEN; identified by tandem affinity purification, WWP2 physically interacts with PTEN and mediates its polyubiquitination and proteasomal degradation; WWP2 controls cellular apoptosis and is required for tumorigenicity. Tandem affinity purification, co-immunoprecipitation, ubiquitination assay, functional apoptosis/tumor assay Nature cell biology High 21532586
2011 WWP2 physically interacts with Sox9 and with Med25 (a Mediator complex component) via a yeast two-hybrid interaction; Wwp2 is associated with Sox9 transcriptional activity through nuclear translocation; morpholino knockdown of wwp2 or med25 in zebrafish induces palatal malformation similar to sox9 mutants, establishing a Sox9–Wwp2–Med25 transcriptional axis in chondrogenesis. Yeast two-hybrid screen, co-immunoprecipitation, morpholino knockdown in zebrafish, reporter assay Nature communications High 21427722
2011 WWP2-FL, WWP2-N, and WWP2-C isoforms selectively interact with different TGFβ pathway Smads: WWP2-FL interacts with Smad2, Smad3, and Smad7; WWP2-N interacts with Smad2 and Smad3; WWP2-C interacts only with Smad7. WWP2-FL and WWP2-C preferentially ubiquitinate and degrade Smad7. WWP2-N, which lacks the HECT domain, dimerizes with WWP2-FL in a TGFβ-regulated manner and activates its ligase activity toward Smad2 and Smad3. These isoforms differentially modulate TGFβ-dependent transcription and EMT. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, EMT reporter assay Oncogene High 21258410
2011 WWP2 binds to ADAR2 and catalyzes its ubiquitination and subsequent degradation, thereby negatively regulating ADAR2 editing activity at the GluR2 Q/R site; Pin1 positively regulates ADAR2 nuclear localization and stability; Pin1-/- MEFs show ADAR2 cytoplasmic mislocalization and reduced editing. Co-immunoprecipitation, ubiquitination assay, Pin1-/- MEF analysis, editing site quantification The EMBO journal High 21847096
2002 WWP2 is expressed in epithelial tissues and its three WW domains (of four) bind differentially to ENaC subunits via their PY motifs; co-expression of WWP2 with ENaC in epithelia inhibits ENaC channel activity in a direct interaction-dependent manner; mutation of ENaC PY motifs abolishes WWP2-mediated inhibition. WW domain-binding assay, electrophysiology in epithelial cells, PY motif mutagenesis American journal of physiology. Renal physiology High 12167593
2013 WWP2 was identified as a TRIF-associated protein by biochemical purification; WWP2 mediates K48-linked polyubiquitination and proteasomal degradation of TRIF upon TLR3 activation; WWP2 overexpression inhibits TLR3-mediated NF-κB and IRF3 activation; Wwp2-deficient mice produce elevated IFN-β, CCL5, TNFα, and IL-6 in response to TLR3 ligand and show increased susceptibility to poly(I:C)-induced death. Biochemical purification, co-immunoprecipitation, K48-linkage specific ubiquitination assay, Wwp2-/- mouse model Proceedings of the National Academy of Sciences of the United States of America High 23479606
2014 WWP2 ubiquitinates and degrades p73; in a heterodimeric complex with WWP1, it specifically ubiquitinates and degrades ΔNp73; the phosphatase PPM1G acts as a functional switch controlling whether WWP2 is monomeric (targeting p73) or in a WWP2/WWP1 heterodimer (targeting ΔNp73), regulating the balance between the two isoforms during cellular stress. Co-immunoprecipitation, ubiquitination assay, phosphatase functional assay, knockdown experiments Molecular and cellular biology High 25071155
2014 WWP2 targets Paip1 (poly(A)-binding protein-interacting protein 1) for ubiquitination and proteasomal degradation via interaction between the WW domain of WWP2 and the PAM2 domain (specifically two consecutive PXXY motifs) of Paip1; WWP2 overexpression decreases translational stimulatory activity of Paip1. Co-immunoprecipitation, ubiquitination assay, domain mapping, translation reporter assay Molecular and cellular biology High 25266661
2014 WWP2 interacts with and ubiquitinates Notch3 intracellular domain (N3-ICD) specifically (not other Notch ICD), causing its mono-ubiquitination and attenuation of Notch3 pathway via endosomal/lysosomal degradation; ligase-deficient WWP2 mutant cannot ubiquitinate N3-ICD; WWP2 expression leads to cell cycle arrest. Protein microarray interactome, co-immunoprecipitation, ubiquitination assay, ligase-dead mutant, lysosomal inhibitor PLoS genetics High 25356737
2015 The HECT domain of human WWP2 was crystallized and its structure solved at 2.5 Å resolution by molecular replacement; the overall structure shows an inverted T-shape with high conservation with other Nedd4 subfamily HECT domains. X-ray crystallography Acta crystallographica. Section F, Structural biology communications High 26457515
2015 Dvl2 (Dishevelled) binds to WWP2 via its PPxY motif and unlocks WWP2 ligase activity from autoinhibition; polymerization of Dvl2 is required for WWP2 disinhibition; activated WWP2 then ubiquitinates Notch intracellular domains, reducing their transcriptional activity; this cross-talk is conserved in Drosophila (Suppressor-of-deltex). Co-immunoprecipitation, ubiquitination assay, Dvl2 polymerization mutants, Drosophila genetic model 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 signaling; the Cdh1-WWP2-PTEN axis is important for tumorigenesis. Co-immunoprecipitation, ubiquitination assay, genetic knockdown/rescue experiments in tumor cells Cell discovery Medium 27462441
2017 WWP2 mono-ubiquitinates RUNX2 in osteoblasts, which leads to RUNX2 transactivation rather than degradation; osteogenic differentiation promotes WWP2 nuclear accumulation; knockdown of Wwp2 in mesenchymal stem cells reduces osteogenesis; BMP receptor signaling regulates the WWP2-RUNX2 axis. Co-immunoprecipitation, ubiquitination assay, WWP2 ligase-dead mutant, reporter assay, knockdown in MSCs The Journal of biological chemistry High 28500134
2018 Itch and WWP2 cooperate as a complex to catalyze atypical ubiquitin chain conjugation to the phosphatase SHP-1, reducing SHP-1 association with Lck and thereby enhancing TCR-proximal signaling; double knockout of Itch and WWP2 in T cells causes spontaneous autoimmunity, TH2 bias, and hypo-responsiveness to TCR stimulation. Co-immunoprecipitation, ubiquitination assay, Itch/WWP2 double-knockout mouse, T cell functional assays Nature immunology High 29925997
2018 WWP2 is a physiological ubiquitin ligase for PTEN in vivo; WWP2 knockout mice show reduced body size, elevated PTEN protein levels, and reduced AKT phosphorylation; CHIP knockout does not affect PTEN levels; CHIP/WWP2 double knockout mirrors WWP2 single knockout, confirming WWP2 as the dominant in vivo E3 ligase for PTEN. WWP2 knockout mice, CHIP knockout mice, CHIP/WWP2 double-knockout mice, tissue protein analysis The Journal of biological chemistry High 29685889
2019 WWP2 associates with components of the DNA-PK and RNAPII complexes; upon DSBs, WWP2 is recruited to DSBs at transcribed genes and targets RPB1 for K48-linked ubiquitylation, driving DNA-PK- and proteasome-dependent eviction of RNAPII; absence of WWP2 or non-ubiquitylatable RPB1 impairs NHEJ factor binding and DSB repair. Co-immunoprecipitation, K48-linkage specific ubiquitination assay, WWP2 knockdown, ChIP, NHEJ repair assay Genes & development High 31048545
2019 Wwp2 ubiquitinates and degrades Runx2 (poly-ubiquitination), reducing Runx2-driven Adamts5 expression in articular cartilage; Wwp2-knockout and Wwp2-C838A catalytic-dead mice exhibit aggravated osteoarthritis; intra-articular injection of Wwp2 mRNA reduces OA severity. Wwp2-/- and Wwp2-C838A knock-in mice, ubiquitination assay, gene expression analysis, mRNA injection experiment Nature communications High 31160553
2019 The WWP2 N-terminal isoform (WWP2-N) specifically promotes cardiac fibrosis; TGFβ1 stimulation promotes nuclear translocation of WWP2-N-containing 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 improved cardiac function and reduced fibrosis after pressure overload or MI. Transgenic mouse model, co-immunoprecipitation, nuclear fractionation, systems genetics Nature communications High 31399586
2019 WWP2 WW domain linker regions (particularly the 2,3-linker) contribute to autoinhibition of the HECT catalytic domain; allosteric activation by NDFIP1 or engineered ubiquitin variants is mediated by relief of WW domain linker autoinhibition; the linker regions influence product distribution including degree of polyubiquitination and K48 vs K63 linkages. In vitro ubiquitination assay, phosphomimetic linker mutants, NDFIP1 binding assay, ubiquitin chain linkage analysis The Journal of biological chemistry High 31578285
2019 NMR structure of the WWP2 WW4 domain solved in solution; WW4 binds Smad7 PPxY peptide, and phosphorylation of Smad7 at serine 206 enhances WW4 binding affinity; WW3 also binds Smad7, with significantly enhanced affinity when expressed in tandem with WW4; a novel WWP2C-ΔHECT isoform (WW3-WW4 + truncated HECT) inhibits TGFβ signaling. NMR spectroscopy, structure determination, peptide binding affinity measurements, functional reporter assay International journal of molecular sciences High 31546607
2020 WWP2 interacts with PARP1 (primarily its BRCT domain) and mediates PARP1 ubiquitination at K418 and K249 and proteasomal degradation; cardiac myocardium-specific WWP2 knockout decreases PARP1 ubiquitination and increases iso-induced PARylation, aggravating cardiac hypertrophy and fibrosis; re-expression of WWP2 in knockdown cells increases PARP1 ubiquitination and decreases PARP1 and PARylation. Cardiac-specific WWP2 knockout, co-immunoprecipitation, ubiquitination assay with site mapping, H9c2 knockdown/re-expression Cell death and differentiation High 32139900
2020 WWP2 interacts with SIRT1 and STAT3, forming a ternary complex; WWP2 inhibits the interaction between SIRT1 and STAT3, reducing SIRT1-mediated deacetylation of STAT3, thereby promoting STAT3-K685 acetylation and STAT3-Y705 phosphorylation in vascular smooth muscle cells; VSMC-specific WWP2 knockout mice show reduced angiotensin II-induced hypertensive angiopathy. Mass spectrometry, co-immunoprecipitation, VSMC-specific WWP2 knockout mouse, phosphorylation/acetylation assays Journal of cellular and molecular medicine High 32627301
2020 WWP2 interacts with BRCC3 deubiquitinase and mediates its ubiquitination and proteasomal degradation; ABRO1 (a BRISC complex subunit) competes with WWP2 to bind BRCC3, preventing WWP2-mediated BRCC3 ubiquitination; WWP2 overexpression in macrophages inhibits NLRP3 inflammasome activation by reducing BRCC3 protein levels. Co-immunoprecipitation, ubiquitination assay, competitive binding assay, NLRP3 inflammasome functional assay FEBS letters High 33107021
2021 WWP2 is a bona fide E3 ligase for SOX2 in glioblastoma stem cells; TRIM26, via its C-terminal PRYSPRY domain (independent of its RING domain), stabilizes SOX2 by directly blocking SOX2's interaction with WWP2; TRIM26 depletion increases SOX2 polyubiquitination and decreases SOX2 protein levels. Proteomic pulldown, co-immunoprecipitation, ubiquitination assay, TRIM26/WWP2 competition assay, GSC self-renewal and tumor assays Nature communications High 34732716
2022 WWP2 is an E3 ligase for the Notch1 intracellular domain (NICD1); NICD1 is ubiquitinated at K1821 by WWP2; the lncRNA BREA2 impairs WWP2-NICD1 complex formation, stabilizing NICD1 and promoting Notch signaling and breast cancer metastasis. Co-immunoprecipitation, ubiquitination assay with site mapping (K1821), lncRNA pulldown, xenograft model Proceedings of the National Academy of Sciences of the United States of America High 36795754
2022 WWP2 interacts with myeloid transcription factor IRF7 and promotes its non-degradative mono-ubiquitination, which drives IRF7 nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 in Ly6chigh monocytes and consequential pro-fibrogenic macrophage infiltration in cardiac fibrosis. Co-immunoprecipitation, mono-ubiquitination assay, nuclear fractionation, myeloid-specific WWP2 KO, single-cell RNA sequencing Nature communications High 36450710
2022 WWP2 is identified as an E3 ligase for autophagy receptors NDP52, OPTN, and SQSTM1; protein microarray with activated WWP2Y369E identified 31 substrate hits; K48-linked ubiquitination sites on these autophagy receptors were mapped by mass spectrometry; WWP2 KO neuroblastoma cells show a defect in mitophagy rescuable by WWP2Y369E transfection. Protein microarray, in vitro ubiquitination assay, mass spectrometry ubiquitin site mapping, CRISPR KO, mitophagy assay The Journal of biological chemistry High 35331737
2013 Mouse Wwp2 forms protein complexes with SRG3 (a scaffold of the SWI/SNF-like BAF complex) via the WW domain of Wwp2 and the PPPY motif of SRG3; Wwp2 and SRG3 co-localize in the nucleus; Wwp2 promotes ubiquitination and proteasomal degradation of SRG3; catalytically inactive Wwp2 mutant abolishes SRG3 ubiquitination. Co-immunoprecipitation, co-localization (nuclear), ubiquitination assay, catalytic mutant Biochemical and biophysical research communications Medium 24365151
2016 WWP2 drives c-Myc ubiquitination and degradation through direct protein-protein interaction following JNK pathway activation; gamabufotalin induces JNK, which upregulates WWP2, which then ubiquitinates c-Myc. Co-immunoprecipitation, ubiquitination assay, JNK inhibitor, xenograft model Oncotarget Medium 26894970
2020 WWP2 promotes mono-ubiquitination of KLF5 in mouse dental papilla cells, leading to KLF5 transactivation (not degradation) and promotion of odontoblastic differentiation; the PPPSY (PY2) motif of KLF5 is required for WWP2 binding; the active site C838 of WWP2 is required for KLF5 ubiquitination; K31, K52, K83, and K265 of KLF5 are the ubiquitination sites. Co-immunoprecipitation, in vitro ubiquitination assay, active-site mutagenesis, motif mutagenesis, ubiquitin site mapping Journal of dental research High 33164644
2022 WWP2 promotes ubiquitination and proteasomal degradation of LATS1 in gastric cancer, leading to increased YAP1 transcriptional activity; WWP2 interacts specifically with LATS1; knockdown of LATS1 abolishes suppressive effects of WWP2 knockdown on cancer cells. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, in vivo xenograft Cell communication and signaling : CCS Medium 36803368
2023 WWP2 interacts with and mediates K63-linked polyubiquitination of DDX3X, targeting it for proteasomal degradation; in high glucose/palmitate-treated endothelial cells, JNK activation downregulates WWP2, leading to DDX3X accumulation and endothelial injury; endothelial-specific WWP2 KO in mice aggravates T2DM-induced vascular endothelial injury. Mass spectrometry substrate identification, co-immunoprecipitation, ubiquitination assay, pulse-chase assay, endothelial-specific KO mice Cardiovascular diabetology High 37149668
2023 Non-receptor tyrosine kinase ACK1 binds to the WW3 domain of WWP2 and phosphorylates WWP2 at the 2,3-linker region to partially activate its ubiquitin ligase activity; EGF stimulates WWP2 tyrosine phosphorylation via ACK1; WWP2 knockdown inhibits EGF-dependent proliferation of lung cancer A549 cells. Co-immunoprecipitation, in vitro kinase assay, phosphomimetic mutants, WWP2 shRNA knockdown, cell proliferation assay IUBMB life Medium 36773333
2024 WWP2 interacts with FACL4 (acyl-CoA synthetase long-chain family member 4) and facilitates its ubiquitin-dependent degradation; WWP2 overexpression suppresses LPS-induced ferroptosis in cardiomyocytes; cardiac-specific WWP2 KO aggravates sepsis-induced ferroptosis and cardiac injury, rescued by FACL4 knockdown. Co-immunoprecipitation, ubiquitination assay, cardiac-specific KO mouse, FACL4 knockdown rescue experiment Journal of translational internal medicine High 38591063
2024 WWP2 is shuttled to mitochondria during AKI-to-CKD transition and ubiquitinates/degrades complex II subunit SDHC, leading to OXPHOS disability; tubular-specific Wwp2 depletion protects against AKI-to-CKD transition; SDHC knockdown abolishes the protective effects of Wwp2 deletion; virtual screening identified two WWP2 inhibitors that improve TEC repair. Tubular-specific Wwp2 KO mice, ubiquitylation omics, quantitative proteomics, co-IP, SDHC knockdown rescue, mitochondrial OXPHOS assay Molecular therapy High 41254942
2025 WWP2 binds TFEB (transcription factor EB) and directly induces TFEB ubiquitination, stabilizing TFEB protein; WWP2 is required for TFEB-dependent host defense response in human monocyte-derived macrophages upon infection; this regulation is evolutionarily conserved (C. elegans WWP-1 regulates TFEB homolog HLH-30). Co-immunoprecipitation, in vitro ubiquitination assay, C. elegans genetic screen, WWP2 KD in human macrophages iScience Medium 39995862
2025 WWP2 promotes ubiquitination and degradation of CDC20 (a negative regulator of autophagy) in renal tubular cells; Wwp2 global or tubular-specific KO aggravates AKI by reducing autophagy; pharmacologic inhibition of CDC20 with apcin rescues the WWP2 KO phenotype; rapamycin (autophagy activator) protects WWP2 KO mice against cisplatin-AKI. Ubiquitylation omics, proteomics, tubular-specific KO mice, CDC20 inhibitor, rapamycin pharmacologic rescue Journal of advanced research High 38909885
2025 NDFIP2 requires multiple PY motifs for interaction with and activation of WWP2; single-PY-motif Ndfips TMEM127 and SUSD6 function as a co-disinhibitory pair to activate WWP2; the Salmonella effector SteD can function as a co-disinhibitory pair with TMEM127 by binding the C2 domain of WWP2, resulting in WWP2 disinhibition. Co-immunoprecipitation, in vitro ubiquitination/activity assay, PY motif mutagenesis, C2 domain interaction mapping The Journal of biological chemistry High 41135677
2025 ARRDC3 harbors a C-terminal PPxY motif that binds WWP2 WW domains; phosphorylation of ARRDC3 at Y394 disrupts ARRDC3-WWP2 interaction and instead promotes ARRDC3 binding to c-Src via its SH2 domain; the non-phosphorylated form of ARRDC3 supports WWP2-dependent lysosomal trafficking of PAR-1 GPCR. Co-immunoprecipitation, phospho-mutant analysis, domain mapping (SH2/WW), GPCR trafficking assay The Journal of biological chemistry Medium 40409556
2025 WWP2 promotes ubiquitination and degradation of BAK (pro-apoptotic BCL2 family member) at K113; oxidative stress weakens the WWP2-BAK interaction and reduces WWP2 expression, suppressing BAK ubiquitination and increasing BAK levels to drive mitochondrial apoptosis in granulosa cells; Wwp2 KO in PCOS mice aggravates granulosa cell apoptosis. Co-immunoprecipitation, ubiquitination assay with site mapping (K113), BAK-K113R mutant, Wwp2 KO in PCOS mouse model Cell death & disease High 41730845
2018 WWP2 and Wwp1 are both required for proper axon-dendrite polarity in developing cortical pyramidal neurons; double knockout of Wwp1 and Wwp2 causes defects in axon specification and aberrant laminar cortical distribution; transcription of Wwp1 and Wwp2/miR-140 loci is induced by Sox9; miR-140 (encoded in Wwp2 intron) supervises polarity through repression of Fyn kinase mRNA. Wwp1/Wwp2 double-knockout mouse, neuronal morphology analysis, Sox9 transcriptional assay, miR-140 functional analysis Neuron High 30392800
2022 WWP2 promotes ubiquitination and degradation of PARP1 via the ubiquitin-proteasome pathway in acute lymphoblastic leukemia cells; WWP2 interacts with PARP1; WWP2 knockout inhibits ALL growth and enhances apoptosis. Co-immunoprecipitation, ubiquitination assay, WWP2 knockout, in vivo xenograft Cell death discovery Medium 36257929
2022 WWP2 interacts with NKRF (NF-κB-repressing factor) via co-immunoprecipitation and promotes NKRF ubiquitylation, thereby enhancing NF-κB signaling and AML cell proliferation; NKRF overexpression abolishes WWP2-driven AML progression. Co-immunoprecipitation, ubiquitination assay, NKRF overexpression rescue experiment Biochemistry and cell biology Medium 37921219
2020 WWP2 interacts with and ubiquitinates p53, promoting its degradation; in ischemia-reperfusion-induced renal tubular cells, WWP2 overexpression promotes proliferation and inhibits apoptosis; the effect is blocked by the proteasome inhibitor MG132. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor, HK-2 cell overexpression Cell biochemistry and function Low 32248569
2021 WWP2 mediates ubiquitination and degradation of GLI2 (Hedgehog transcription factor); DKK1 suppresses WWP2 expression via Wnt/β-catenin signaling, thereby stabilizing GLI2 and activating Hh signaling to confer bortezomib resistance in multiple myeloma. Co-immunoprecipitation, ubiquitination assay, WWP2 overexpression, in vivo xenograft Carcinogenesis Medium 34546340
2022 WWP2 interacts with and ubiquitinates PDCD4, promoting its degradation; WWP2 overexpression attenuates ox-LDL-induced HUVEC oxidative stress and inflammation via the PDCD4/HO-1 pathway; knockdown of PDCD4 alleviates WWP2 knockdown-induced endothelial injury. Co-immunoprecipitation, ubiquitination assay, PDCD4 knockdown rescue, HO-1 inhibitor experiment Acta biochimica et biophysica Sinica Medium 35983977
2023 MEF2A transcriptionally activates WWP2 expression; WWP2 promotes ubiquitination and degradation of SH2B3 in microglia; MEF2A overexpression or SH2B3 knockdown restores microglial homeostasis and ameliorates ischemic stroke injury; SH2B3 overexpression reverses MEF2A effects. ChIP assay, dual-luciferase reporter, co-immunoprecipitation, ubiquitination assay, MCAO in vivo model Neurochemical research Medium 40407948
2025 WWP2 promotes K48-linked ubiquitination and proteasomal degradation of p21, leading to inhibition of cellular senescence in HCC; CMTM6 directly interacts with WWP2 and stabilizes p21 by preventing its WWP2-mediated ubiquitination; WWP2 depletion induces senescence and suppresses HCC tumor growth in vivo. Co-immunoprecipitation, ubiquitination assay, competitive binding assay, in vivo tumor model Cell death & disease High 41387673

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 307 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 124 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
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
2020 Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling. Cell death and differentiation 102 32139900
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 90 31160553
2009 Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner. Cell research 82 19997087
2019 WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks. Genes & development 80 31048545
2011 Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT. Oncogene 73 21258410
2014 Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer. PLoS genetics 66 25356737
2007 Wwp2-mediated ubiquitination of the RNA polymerase II large subunit in mouse embryonic pluripotent stem cells. Molecular and cellular biology 64 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 58 36795754
2019 WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature communications 58 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 51 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 47 28500134
2018 The E3 ligases Itch and WWP2 cooperate to limit TH2 differentiation by enhancing signaling through the TCR. Nature immunology 39 29925997
2016 Cdh1 inhibits WWP2-mediated ubiquitination of PTEN to suppress tumorigenesis in an APC-independent manner. Cell discovery 39 27462441
2015 Disinhibition of the HECT E3 ubiquitin ligase WWP2 by polymerized Dishevelled. Open biology 39 26701932
2022 The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis. Nature communications 37 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 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
2019 Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases. The Journal of biological chemistry 29 31578285
2024 WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts. Journal of the American Society of Nephrology : JASN 28 38502123
2011 WWP2 ubiquitin ligase and its isoforms: new biological insight and promising disease targets. Cell cycle (Georgetown, Tex.) 26 21750408
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 25 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 25 31837982
2023 WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein. Cell communication and signaling : CCS 24 36803368
2023 Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X. Cardiovascular diabetology 24 37149668
2016 Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells. Oncotarget 23 26894970
2019 WWP2 regulates proliferation of gastric cancer cells in a PTEN-dependent manner. Biochemical and biophysical research communications 21 31677789
2016 Inhibition of WWP2 suppresses proliferation, and induces G1 cell cycle arrest and apoptosis in liver cancer cells. Molecular medicine reports 21 26783238
2015 WWP2 and its association with PTEN in endometrial cancer. Gynecologic oncology reports 21 26425715
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
2024 WWP2 protects against sepsis-induced cardiac injury through inhibiting cardiomyocyte ferroptosis. Journal of translational internal medicine 19 38591063
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
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 Functional analyses of an E3 ligase gene AIP2 from wheat in Arabidopsis revealed its roles in seed germination and pre-harvest sprouting. Journal of integrative plant biology 17 24279988
2014 Paip1, an effective stimulator of translation initiation, is targeted by WWP2 for ubiquitination and degradation. Molecular and cellular biology 17 25266661
2022 WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma. Cell biology international 16 35880837
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
2020 ABRO1 stabilizes the deubiquitinase BRCC3 through inhibiting its degradation mediated by the E3 ubiquitin ligase WWP2. FEBS letters 15 33107021
2022 Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates. The Journal of biological chemistry 14 35331737
2021 DKK1 suppresses WWP2 to enhance bortezomib resistance in multiple myeloma via regulating GLI2 ubiquitination. Carcinogenesis 14 34546340
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 RNAi and CRISPR-Cas silencing E3-RING ubiquitin ligase AIP2 enhances soybean seed protein content. Journal of experimental botany 13 36112496
2022 WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway. Acta biochimica et biophysica Sinica 12 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
2015 WWP2 is required for normal cell cycle progression. Genes & cancer 11 26622940
2020 WWP2 ameliorates acute kidney injury by mediating p53 ubiquitylation and degradation. Cell biochemistry and function 10 32248569
2024 E3 ubiquitin ligase WWP2 as a promising therapeutic target for diverse human diseases. Molecular aspects of medicine 9 38430667
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
2023 Atorvastatin rescues vascular endothelial injury in hypertension by WWP2-mediated ubiquitination and degradation of ATP5A. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 37557013
2022 The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia. Cell death discovery 8 36257929
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
2024 WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis. Journal of advanced research 6 38909885
2015 Characterization of substrate binding of the WW domains in human WWP2 protein. FEBS letters 6 25999310
2023 Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1. IUBMB life 5 36773333
2025 Sculponeatin A induces mitochondrial dysfunction in non-small cell lung cancer through WWP2-mediated degradation of mitochondrial STAT3. British journal of pharmacology 4 39993792
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 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
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 DEF6 regulates renal ischemia reperfusion injury through suppressing the WWP2 mediated ubiquitination of PARP1. Biochimica et biophysica acta. Molecular basis of disease 1 39837430
2025 Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo. iScience 1 39995862
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
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 1 37870050
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
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 Mammalian and bacterial adaptors function as co-disinhibitory pairs to activate the E3 ubiquitin ligase WWP2. The Journal of biological chemistry 0 41135677
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 0 41350729
2025 WWP2-induced inhibition of hepatocellular carcinoma cellular senescence via the ubiquitination and degradation of p21. Cell death & disease 0 41387673