BioPAX pathway converted from "NOTCH3 binds WWP2" in the Reactome database. LEFT-TO-RIGHT NOTCH3 binds WWP2 WWP2, an E3 ubiquitin ligase, can interact with NOTCH3 cleavage products NEXT3 and NICD3 in the cytosol. The interaction involves the PPPY motif in the PEST domain of NOTCH3 (Jung et al. 2014). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 AIP2 Atrophin-1-interacting protein 2 WW domain-containing protein 2 Reactome DB_ID: 6807279 cytosol GENE ONTOLOGY GO:0005829 UniProt:O00308 WWP2 WWP2 FUNCTION 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. 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.ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity). Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 AND NDFIP2. Interacts with ARRDC4 (PubMed:23236378). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains) with ARRDC2 and ARRDC3 (PubMed:21191027).SUBUNIT (Microbial infection) Interacts with adenovirus type 2 PIII.TISSUE SPECIFICITY Detected in heart, throughout the brain, placenta, lung, liver, muscle, kidney and pancreas. Also detected in spleen and peripheral blood leukocytes.DEVELOPMENTAL STAGE Highly expressed in undifferentiated embryonic stem cells and expression is reduced after embryoid body (EB) formation. Not detectable at day 13 of EB formation; low levels are again detected at day 18 of EB formation.DOMAIN The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.DOMAIN The WW domains mediate interaction with PPxY motif-containing proteins.PTM Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.MISCELLANEOUS A cysteine residue is required for ubiquitin-thioester formation. Homo sapiens NCBI Taxonomy 9606 UniProt O00308 1 EQUAL 870 EQUAL Reactome Database ID Release 82 6807279 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807279 Reactome R-HSA-6807279 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6807279.1 Reactome http://www.reactome.org Converted from EntitySet in Reactome NEXT3,NICD3 Reactome DB_ID: 9021530 NEXT3 NOTCH3(1629-2321) Notch 3 NEXT fragment Reactome DB_ID: 157203 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q9UM47 NOTCH3 NOTCH3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1. Interacts with HIF1AN.TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.DOMAIN The EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family. UniProt Q9UM47 1629 EQUAL 2321 EQUAL Reactome Database ID Release 82 157203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157203 Reactome R-HSA-157203 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157203.1 NICD3 NOTCH3(1662-2321) NICD 3 fragment N3ICD Reactome DB_ID: 157647 1662 EQUAL 2321 EQUAL Reactome Database ID Release 82 157647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157647 Reactome R-HSA-157647 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157647.1 Reactome Database ID Release 82 9021530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9021530 Reactome R-HSA-9021530 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9021530.2 NEXT3,NICD3:WWP2 Reactome DB_ID: 9021521 1 1 Reactome Database ID Release 82 9021521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9021521 Reactome R-HSA-9021521 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9021521.1 Reactome Database ID Release 82 9021520 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9021520 Reactome R-HSA-9021520 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9021520.1 25356737 Pubmed 2014 Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer Jung, Jin-Gyoung Stoeck, Alexander Guan, Bin Wu, Ren-Chin Zhu, Heng Blackshaw, S Shih, Ie-Ming Wang, Tian-Li PLoS Genet. 10:e1004751 GENE ONTOLOGY GO:0045746 gene ontology term for cellular process MI MI:0359