BioPAX pathway converted from "NOTCH3 binds WWP2" in the Reactome database. NOTCH3 binds WWP2 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 Reactome DB_ID: 6807279 1 cytosol GO 0005829 UniProt:O00308 WWP2 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. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O00308 Chain Coordinates 1 EQUAL 870 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9021530 1 NEXT3,NICD3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NICD3 [cytosol] NEXT3 [plasma membrane] UniProt Q9UM47 Reactome DB_ID: 9021521 1 NEXT3,NICD3:WWP2 [cytosol] NEXT3,NICD3:WWP2 Reactome DB_ID: 6807279 1 1 EQUAL 870 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9021530 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 GO 0045746 GO biological process