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The 24 function of WW of the protein

S.NOUniprot IDProtein Name Sequence LengthWW Repeated RegionFunction
1 Q9HAU4 E3 ubiquitin-protein ligase SMURF2 748"E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation.
In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1.
Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3.
In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation.
Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2.
Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level".
2 Q9HCE7 E3 ubiquitin-protein ligase SMURF1 757"E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway.
Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway.
Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA.
Promotes ubiquitination and subsequent proteasomal degradation of MAVS (PubMed:23087404).
Plays a role in dendrite formation by melanocytes (PubMed:23999003)".
3 Q8IWW6 Rho GTPase-activating protein 12 846GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
4 O75554 WW domain-binding protein 4 376"Involved in pre-mRNA splicing as a component of the spliceosome (PubMed:9724750, PubMed:19592703, PubMed:28781166).
May play a role in cross-intron bridging of U1 and U2 snRNPs in the mammalian A complex (PubMed:9724750)".
5 O14776 Transcription elongation regulator 1 1098Transcription factor that binds RNA polymerase II and inhibits the elongation of transcripts from target promoters.
Regulates transcription elongation in a TATA box-dependent manner.
Necessary for TAT-dependent activation of the human immunodeficiency virus type 1 (HIV-1) promoter.
6 O75400 Pre-mRNA-processing factor 40 homolog A 957"Binds to WASL/N-WASP and suppresses its translocation from the nucleus to the cytoplasm, thereby inhibiting its cytoplasmic function (By similarity).
Plays a role in the regulation of cell morphology and cytoskeletal organization.
Required in the control of cell shape and migration.
May play a role in cytokinesis.
May be involved in pre-mRNA splicing".
7 Q9NZC7 WW domain-containing oxidoreductase 414"Putative oxidoreductase.
Acts as a tumor suppressor and plays a role in apoptosis.
Required for normal bone development (By similarity).
May function synergistically with p53/TP53 to control genotoxic stress-induced cell death.
Plays a role in TGFB1 signaling and TGFB1-mediated cell death.
May also play a role in tumor necrosis factor (TNF)-mediated cell death.
Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm".
8 Q86UL8 "Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 "1455Seems to act as scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins.
May play a role in regulating activin-mediated signaling in neuronal cells.
Enhances the ability of PTEN to suppress AKT1 activation.
Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth.
9 Q96QZ7 "Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 "1491May play a role as scaffolding protein at cell-cell junctions.
May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity).
10 P46937 Transcriptional coactivator YAP1 504"Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637).
The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288).
Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation.
Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702).
Plays a key role to control cell proliferation in response to cell contact.
Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288).
The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750).
; Isoform 2: Isoform 2 and isoform 3 can activate the C-terminal fragment (CTF) of ERBB4 (isoform 3)".
11 Q9P2P5 E3 ubiquitin-protein ligase HECW2 1572E3 ubiquitin-protein ligase that mediates ubiquitination of TP73.
Acts to stabilize TP73 and enhance activation of transcription by TP73 (PubMed:12890487).
Involved in the regulation of mitotic metaphase/anaphase transition (PubMed:24163370).
12 Q5TCQ9 "Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 "1481"Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes.
Cooperates with PTEN to modulate the kinase activity of AKT1.
Its interaction with PTPRB and tyrosine phosphorylated proteins suggests that it may link receptor tyrosine phosphatase with its substrates at the plasma membrane.
In polarized epithelial cells, involved in efficient trafficking of TGFA to the cell surface.
Regulates the ability of LPAR2 to activate ERK and RhoA pathways.
Regulates the JNK signaling cascade via its interaction with FZD4 and VANGL2".
13 Q76N89 E3 ubiquitin-protein ligase HECW1 1606"E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent degradation of DVL1.
Also targets the mutant SOD1 protein involved in familial amyotrophic lateral sclerosis (FALS).
Forms cytotoxic aggregates with DVL1, SSR3 and mutant SOD1 that lead to motor neuron death in FALS".
14 Q9H4B6 Protein salvador homolog 1 383"Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ.
Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration.
SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues.
Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250.
In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation".
15 O00308 NEDD4-like E3 ubiquitin-protein ligase WWP2 870E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level.
Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death.
Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2.
Ubiquitinates RPB1 and promotes it to proteasomal degradation.
16 O95817 BAG family molecular chaperone regulator 3 575"Co-chaperone for HSP70 and HSC70 chaperone proteins.
Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release.
Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:9873016, PubMed:27474739).
Has anti-apoptotic activity (PubMed:10597216).
Plays a role in the HSF1 nucleocytoplasmic transport (PubMed:26159920)".
17 Q9H0M0 NEDD4-like E3 ubiquitin-protein ligase WWP1 922"E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation.
Ubiquitinates RNF11 without targeting it for degradation.
Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7.
Ubiquitinates SMAD6 and SMAD7.
Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF".
18 Q96J02 E3 ubiquitin-protein ligase Itchy homolog 903"Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046).
Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509).
Involved in the control of inflammatory signaling pathways (PubMed:19131965).
Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965).
Promotes the association of the complex after TNF stimulation (PubMed:19131965).
Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965).
This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965).
Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251).
Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914).
Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448).
Mediates JUN ubiquitination and degradation (By similarity).
Mediates JUNB ubiquitination and degradation (PubMed:16387660).
Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity).
Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509).
Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509).
Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885).
Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885).
Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, PubMed:23146885).
Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940).
Ubiquitinates SNX9 (PubMed:20491914).
Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity).
Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034).
Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206).
Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046)".
19 Q8IX03 Protein KIBRA 1113"Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis.
Along with NF2 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway.
Acts as a transcriptional coactivator of ESR1 which plays an essential role in DYNLL1-mediated ESR1 transactivation.
Regulates collagen-stimulated activation of the ERK/MAPK cascade.
Modulates directional migration of podocytes.
Acts as a substrate for PRKCZ.
Plays a role in cognition and memory performance".
20 Q6ZUM4 Rho GTPase-activating protein 27 889Rho GTPase-activating protein which may be involved in clathrin-mediated endocytosis.
GTPase activators for the Rho-type GTPases act by converting them to an inactive GDP-bound state.
Has activity toward CDC42 and RAC1 (By similarity).
21 P46934 E3 ubiquitin-protein ligase NEDD4 1319"E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Specifically ubiquitinates 'Lys-63' in target proteins (PubMed:23644597).
Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity.
Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes.
Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes.
Promotes ubiquitination of RAPGEF2.
According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable.
Involved in ubiquitination of ERBB4 intracellular domain E4ICD.
Involved in the budding of many viruses.
Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development.
Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2.
Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).
; (Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding".
22 Q96PU5 E3 ubiquitin-protein ligase NEDD4-like 975"E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation.
Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.
2, SCN3A/Nav1.
3, SCN5A/Nav1.
5, SCN9A/Nav1.
7, SCN10A/Nav1.
8, KCNA3/Kv1.
3, KCNH2, EAAT1, KCNQ2/Kv7.
2, KCNQ3/Kv7.
3 or CLC5 (PubMed:26363003, PubMed:27445338).
Promotes ubiquitination and degradation of SGK1 and TNK2.
Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).
Plays a role in dendrite formation by melanocytes (PubMed:23999003).
Involved in the regulation of TOR signaling (PubMed:27694961).
Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338)".
23 Q6IQ23 Pleckstrin homology domain-containing family A member 7 1121"Required for zonula adherens biogenesis and maintenance.
Acts via its interaction with KIAA1543/Nezha, which anchors microtubules at their minus-ends to zonula adherens, leading to the recruitment of KIFC3 kinesin to the junctional site".
24 Q6NWY9 Pre-mRNA-processing factor 40 homolog B 871May be involved in pre-mRNA splicing.