BioPAX pathway converted from "Signaling by NOTCH4" in the Reactome database. Signaling by NOTCH4 The NOTCH4 gene locus was discovered as a frequent site of insertion for the proviral genome of the mouse mammary tumor virus (MMTV) (Gallahan and Callahan 1987). MMTV-insertion results in aberrant expression of the mouse mammary tumor gene int-3, which was subsequently discovered to represent the intracellular domain of Notch4 (Robbins et al. 1992, Uyttendaele et al. 1996).<br><br>NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). NICD4 traffics to the nucleus where it acts as a transcription factor and stimulates expression of NOTCH target genes HES1, HES5, HEY1 and HEY2, as well as VEGFR3 and ACTA2 (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Shawber et al. 2007, Tang et al. 2008, Bargo et al. 2010). NOTCH4 signaling can be downregulated by AKT1 phosphorylation-induced cytoplasmic retention (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).<br><br>NOTCH4 was reported to inhibit NOTCH1 signaling in-cis, by binding to NOTCH1 and interfering with the S1 cleavage of NOTCH1, thus preventing production of functional NOTCH1 heterodimers at the cell surface (James et al. 2014).<br><br>NOTCH4 is involved in development of the vascular system. Overexpression of constitutively active Notch4 in mouse embryonic vasculature results in abnormal vessel structure and patterning (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).<br><br>Expression of int-3 interferes with normal mammary gland development in mice and promotes tumorigenesis. The phenotype of mice expressing int-3 in mammary glands is dependent on the presence of Rbpj (Raafat et al. 2009). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with elevated expression of NOTCH target genes HES1, HEY1 and HEY2, and is associated with increased population of breast cancer stem cells and distant metastases (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). In head and neck squamous cell carcinoma (HNSCC), high NOTCH4 expression correlates with elevated HEY1 levels, increased cell proliferation and survival, epithelial-to-mesenchymal transition (EMT) phenotype and cisplatin resistance (Fukusumi et al. 2018). In melanoma, however, exogenous NOTCH4 expression correlates with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). NOTCH4 is frequently overexpressed in gastric cancer. Increased NOTCH4 levels correlate with activation of WNT signaling and gastric cancer progression (Qian et al. 2015).<br><br>NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).<br><br>During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, M, 2012-02-10 Edited: Orlic-Milacic, Marija, 2018-05-09 NOTCH4 Activation and Transmission of Signal to the Nucleus NOTCH4 is co-expressed with DLL4 (Delta-4) and JAG1 (Jagged-1) in the vascular system (Shutter et al. 2000, Uyttendaele et al. 2000). NOTCH4 can be activated by DLL4 and JAG1 when HMVECd cells (human primary endothelial cell line derived from neonatal dermal microvasculature) or HUVEC cells (human umbilical venous endothelial cell line) expressing recombinant mouse Notch4 are co-cultured with HMVECd or HUVEC cells expressing recombinant human or mouse DLL4 (Shawber et al. 2003, Shawber et al. 2007) or mouse Jag1 (Shawber et al. 2007). Activation of NOTCH4 by DLL4 and JAG1 could not be reproduced when the mouse fibroblast cell line NIH 3T3 or human embryonic kidney cell line HEK293 was transduced with Notch4- or either Dll4- or Jag1-expressing vectors and used in co-culture experiments (Aste-Amezaga et al. 2010, James et al. 2014).<br><br>Signaling by NOTCH4, similar to other NOTCH family proteins, involves proteolytic cleavage of the membrane-bound NOTCH4 receptor and release of the NOTCH4 intracellular domain fragment (NICD4) into the cytosol (Saxena et al. 2001, Das et al. 2004). NICD4 traffics from the cytosol to the nucleus, where it acts as a transcription factor (Lin et al. 2002). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 LEFT-TO-RIGHT DLL4 binds NOTCH4 Both DLL4 and NOTCH4 are strongly expressed in the vascular endothelium and DLL4 is able to activate NOTCH4 signaling (Shutter et al. 2000, Shawber et al. 2003, Shawber et al. 2007). In mice, Notch4 and Dll4 are specifically expressed in arterial endothelial cells, and Dll4 is required for normal arterial patterning and development (Duarte et al. 2004). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Reviewed: Joutel, A, 2004-12-15 Edited: Orlic-Milacic, Marija, 2018-05-09 DLL4 Delta 4 ligand Reactome DB_ID: 158437 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q9NR61 DLL4 DLL4 UNQ1895/PRO4341 FUNCTION Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).SUBUNIT Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).TISSUE SPECIFICITY Expressed in vascular endothelium.DOMAIN The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor. Homo sapiens NCBI Taxonomy 9606 UniProt Q9NR61 27 EQUAL 685 EQUAL Reactome Database ID Release 81 158437 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=158437 Reactome R-HSA-158437 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-158437.1 Reactome http://www.reactome.org NOTCH4 NTM-NEC 4 heterodimer Reactome DB_ID: 157053 NOTCH4(1337-2003) Notch 4 Transmembrane fragment (NTMIC4) Reactome DB_ID: 157213 UniProt:Q99466 NOTCH4 NOTCH4 INT3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. 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. May regulate branching morphogenesis in the developing vascular system (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 NOTCH4.TISSUE SPECIFICITY Highly expressed in the heart, moderately in the lung and placenta and at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow and fetal liver. No expression was seen in adult brain or peripheral blood leukocytes.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 (By similarity).PTM Phosphorylated.POLYMORPHISM The poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic and the number of Leu varies in the population (from 6 to 12).SIMILARITY Belongs to the NOTCH family. UniProt Q99466 1337 EQUAL 2003 EQUAL Reactome Database ID Release 81 157213 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=157213 Reactome R-HSA-157213 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-157213.1 1 NOTCH4 Extracellular fragment (NECD4) 12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) Reactome DB_ID: 1983677 extracellular region GENE ONTOLOGY GO:0005576 40 EQUAL O-fucosyl-L-threonine MOD MOD:00813 79 EQUAL O-fucosyl-L-serine MOD MOD:00812 210 EQUAL 248 EQUAL 290 EQUAL 331 EQUAL 369 EQUAL 451 EQUAL 489 EQUAL 603 EQUAL 705 EQUAL 743 EQUAL 781 EQUAL 820 EQUAL 944 EQUAL 982 EQUAL 1060 EQUAL 1145 EQUAL 398 EQUAL O-glucosyl-L-serine MOD MOD:00804 481 EQUAL 519 EQUAL 557 EQUAL 595 EQUAL 697 EQUAL 735 EQUAL 773 EQUAL 936 EQUAL 974 EQUAL 1052 EQUAL 24 EQUAL 1336 EQUAL Reactome Database ID Release 81 1983677 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=1983677 Reactome R-HSA-1983677 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-1983677.1 1 Reactome Database ID Release 81 157053 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=157053 Reactome R-HSA-157053 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-157053.1 DLL4:NOTCH4 Reactome DB_ID: 2105041 1 1 Reactome Database ID Release 81 2105041 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=2105041 Reactome R-HSA-2105041 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-2105041.1 Reactome Database ID Release 81 2168987 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=2168987 Reactome R-HSA-2168987 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-2168987.1 15466159 Pubmed 2004 Dosage-sensitive requirement for mouse Dll4 in artery development Duarte, A Hirashima, Masanori Benedito, R Trindade, Alexandre Diniz, Patrícia Bekman, Evguenia Costa, Luís Henrique, Domingos Rossant, Janet Genes Dev. 18:2474-8 17948123 Pubmed 2007 Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression Shawber, Carrie J Funahashi, Y Francisco, Esther Vorontchikhina, Marina Kitamura, Yukari Stowell, Stephanie A Borisenko, Valeriya Feirt, Nikki Podgrabinska, Simona Shiraishi, Kazuko Chawengsaksophak, Kallayanee Rossant, Janet Accili, D Skobe, Mihaela Kitajewski, J J. Clin. Invest. 117:3369-82 12814948 Pubmed 2003 Notch signaling in primary endothelial cells Shawber, Carrie J Das, I Francisco, Esther Kitajewski, J Ann. N. Y. Acad. Sci. 995:162-70 10837024 Pubmed 2000 Dll4, a novel Notch ligand expressed in arterial endothelium Shutter, JR Scully, S Fan, W Richards, WG Kitajewski, J Deblandre, GA Kintner, CR Stark, KL Genes Dev 14:1313-8 GENE ONTOLOGY GO:0045747 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT JAG1 binds NOTCH4 JAG1 can activate NOTCH4 signaling, based on co-culture of JAG1-expressing and NOTCH4 expressing HUVEC cells (human umbilical vein endothelial cell line) (Shawber et al. 2007). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with an increase in population of breast cancer stem cells (Simoes et al. 2015). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 JAG1 Jagged 1 ligand Reactome DB_ID: 157098 UniProt:P78504 JAG1 JAG1 JAGL1 FUNCTION Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).SUBUNIT Interacts with NOTCH2 and NOTCH3 (By similarity). Interacts with NOTCH1 (in the presence of calcium ions) (PubMed:18660822).TISSUE SPECIFICITY Widely expressed in adult and fetal tissues. In cervix epithelium expressed in undifferentiated subcolumnar reserve cells and squamous metaplasia. Expression is up-regulated in cervical squamous cell carcinoma. Expressed in bone marrow cell line HS-27a which supports the long-term maintenance of immature progenitor cells.DEVELOPMENTAL STAGE Expressed in 32-52 days embryos in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube.DOMAIN The second EGF-like domain is atypical. UniProt P78504 34 EQUAL 1218 EQUAL Reactome Database ID Release 81 157098 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=157098 Reactome R-HSA-157098 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-157098.1 JAG1:NOTCH4 Reactome DB_ID: 9604245 1 1 Reactome Database ID Release 81 9604245 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=9604245 Reactome R-HSA-9604245 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-9604245.1 Reactome Database ID Release 81 9604247 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=9604247 Reactome R-HSA-9604247 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-9604247.1 26387946 Pubmed 2015 Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity Simões, Bruno M O'Brien, Ciara S Eyre, Rachel Silva, Andreia Yu, Ling Sarmiento-Castro, Aida Alférez, Denis G Spence, Kath Santiago-Gómez, Angélica Chemi, Francesca Acar, Ahmet Gandhi, Ashu Howell, Anthony Brennan, Keith Rydén, Lisa Catalano, Stefania Andó, Sebastiano Gee, Julia Ucar, Ahmet Sims, Andrew H Marangoni, Elisabetta Farnie, Gillian Landberg, Göran Howell, Sacha J Clarke, Robert B Cell Rep 12:1968-77 LEFT-TO-RIGHT ADAM10 cleaves NOTCH4 Based on sequence similarity with other NOTCH family members and the requirement for knockout of both Notch1 and Notch4 in endothelial cells to recapitulate vasculature defects seen upon endothelial cell-specific Adam10 knockout, it is plausible that ADAM10 cleaves ligand-activated NOTCH4, releasing the membrane-bound NEXT4 fragment (Alabi et al. 2016). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 Converted from EntitySet in Reactome DLL4:NOTCH4,JAG1:NOTCH4 Reactome DB_ID: 9604269 Reactome Database ID Release 81 9604269 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=9604269 Reactome R-HSA-9604269 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-9604269.1 NEXT4 NOTCH4(1432-2003) Notch 4 NEXT fragment Reactome DB_ID: 157641 1432 EQUAL 2003 EQUAL Reactome Database ID Release 81 157641 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=157641 Reactome R-HSA-157641 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-157641.2 ACTIVATION ADAM10:Zn2+ ADAM 10 metalloprotease (Zn cofactor) Reactome DB_ID: 157186 Zn2+ Zn++ zinc(2+) zinc Zn(II) Reactome DB_ID: 109265 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 109265 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=109265 Reactome R-ALL-109265 3 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-ALL-109265.3 COMPOUND C00038 additional information MI MI:0361 1 KUZ ADAM10 ADAM 10 metalloprotease Reactome DB_ID: 157237 UniProt:O14672 ADAM10 ADAM10 KUZ MADM FUNCTION Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).FUNCTION (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.ACTIVITY REGULATION Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781).SUBUNIT Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells (PubMed:16239146). Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens (PubMed:30463011). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (PubMed:26686862, PubMed:26668317). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (PubMed:26686862). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (PubMed:30312582).SUBUNIT (Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.TISSUE SPECIFICITY Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).INDUCTION In osteoarthritis affected-cartilage.DOMAIN The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.DOMAIN The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).PTM The precursor is cleaved by furin and PCSK7. UniProt O14672 214 EQUAL 748 EQUAL Reactome Database ID Release 81 157237 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=157237 Reactome R-HSA-157237 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-157237.1 1 Reactome Database ID Release 81 157186 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=157186 Reactome R-HSA-157186 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-157186.2 GENE ONTOLOGY GO:0008237 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 157208 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=157208 Reactome Database ID Release 81 9604264 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=9604264 Reactome R-HSA-9604264 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-9604264.1 27354212 Pubmed 2016 ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds Alabi, Rolake O Glomski, Krzysztof Haxaire, Coline Weskamp, Gisela Monette, Sébastien Blobel, Carl P Circ. Res. 119:519-31 GENE ONTOLOGY GO:0035333 LEFT-TO-RIGHT 3.4.23.32 3.4.23.43 3.4.23.20 3.4.23.25 3.4.23.36 3.4.23.35 3.4.23.34 3.4.23.4 3.4.23.5 3.4.23.1 3.4.23.15 Gamma-secretase cleaves NOTCH4 NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which releases the intracellular domain NICD4 into the cytosol (Saxena et al. 2001, Das et al. 2004). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 NICD4 NOTCH4(1467-2003) NICD 4 fragment N4ICD Reactome DB_ID: 157636 cytosol GENE ONTOLOGY GO:0005829 1467 EQUAL 2003 EQUAL Reactome Database ID Release 81 157636 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=157636 Reactome R-HSA-157636 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-157636.1 TM4 NOTCH4(1432-1466) Transmembrane remnant 4 Reactome DB_ID: 157635 1432 EQUAL 1466 EQUAL Reactome Database ID Release 81 157635 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=157635 Reactome R-HSA-157635 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-157635.1 ACTIVATION activeUnit: #Complex7 gamma-secretase complex Reactome DB_ID: 157343 Converted from EntitySet in Reactome PSEN Presenilin Reactome DB_ID: 9013333 PSEN2 PSEN2 dimer Presenilin-2 Reactome DB_ID: 157352 PSEN2(1-297) PSEN2 N-terminal fragment Presenilin-2 NTF subunit Reactome DB_ID: 201599 UniProt:P49810 PSEN2 PSEN2 AD4 PS2 PSNL2 STM2 FUNCTION Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369).SUBUNIT Interacts with DOCK3 (By similarity). Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.TISSUE SPECIFICITY Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.DOMAIN The PAL motif is required for normal active site conformation.PTM Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.PTM Phosphorylated on serine residues.SIMILARITY Belongs to the peptidase A22A family. UniProt P49810 1 EQUAL 297 EQUAL Reactome Database ID Release 81 201599 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=201599 Reactome R-HSA-201599 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-201599.2 1 PSEN2(298-448) PSEN2 C-terminal fragment Presenilin-2 CTF subunit Reactome DB_ID: 9013329 298 EQUAL 448 EQUAL Reactome Database ID Release 81 9013329 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=9013329 Reactome R-HSA-9013329 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-9013329.1 1 Reactome Database ID Release 81 157352 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=157352 Reactome R-HSA-157352 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-157352.2 PS1 PSEN1 Presenillin-1 PSEN1 dimer Reactome DB_ID: 2534316 PSEN1(299-467) Presenilin-1 C-terminal fragment Presenilin-1 CTF subunit Reactome DB_ID: 2534245 UniProt:P49768 PSEN1 PSEN1 AD3 PS1 PSNL1 FUNCTION Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).SUBUNIT Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:25394380, PubMed:30598546, PubMed:30630874). Such minimal complex is sufficient for secretase activity (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632). Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (via transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation (PubMed:11953314). Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:9738936, PubMed:9437013, PubMed:10551805, PubMed:10037471, PubMed:11953314, PubMed:11799129, PubMed:16126725). Interacts through its N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with DOCK3 (By similarity). Interacts with isoform 1 and isoform 3 of UBQLN1 (PubMed:21143716).TISSUE SPECIFICITY Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) (PubMed:11987239). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442, PubMed:8574969).DOMAIN The PAL motif is required for normal active site conformation.DOMAIN Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.PTM Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.PTM After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.SIMILARITY Belongs to the peptidase A22A family. UniProt P49768 299 EQUAL 467 EQUAL Reactome Database ID Release 81 2534245 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=2534245 Reactome R-HSA-2534245 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-2534245.2 1 PSEN1(1-298) Presenilin-1 N-terminal fragment presenilin-1 NTF subunit Reactome DB_ID: 2534298 1 EQUAL 298 EQUAL Reactome Database ID Release 81 2534298 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=2534298 Reactome R-HSA-2534298 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-2534298.2 1 Reactome Database ID Release 81 2534316 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=2534316 Reactome R-HSA-2534316 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-2534316.2 Reactome Database ID Release 81 9013333 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=9013333 Reactome R-HSA-9013333 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-9013333.1 1 Converted from EntitySet in Reactome APH-1 Reactome DB_ID: 157341 APH1B APH-1B Reactome DB_ID: 157340 UniProt:Q8WW43 APH1B APH1B PSFL UNQ688/PRO1328 FUNCTION Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.SUBUNIT Probable component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist (By similarity). Interacts with PSEN1 and PSEN2.TISSUE SPECIFICITY Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.SIMILARITY Belongs to the APH-1 family. UniProt Q8WW43 1 EQUAL 257 EQUAL Reactome Database ID Release 81 157340 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=157340 Reactome R-HSA-157340 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-157340.1 APH1A Gamma-secretase subunit APH-1A APH1A_HUMAN Reactome DB_ID: 3211581 UniProt:Q96BI3 APH1A APH1A PSF CGI-78 UNQ579/PRO1141 FUNCTION Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12297508, PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:30598546, PubMed:30630874).TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.SIMILARITY Belongs to the APH-1 family. UniProt Q96BI3 1 EQUAL 265 EQUAL Reactome Database ID Release 81 3211581 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=3211581 Reactome R-HSA-3211581 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-3211581.1 Reactome Database ID Release 81 157341 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=157341 Reactome R-HSA-157341 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-157341.1 1 PEN-2 PSENEN Reactome DB_ID: 157331 UniProt:Q9NZ42 PSENEN PSENEN PEN2 MDS033 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.SIMILARITY Belongs to the PEN-2 family.CAUTION The high-resolution electron microscopy structures indicate that the N-terminus is cytoplasmic, followed by two short helices that dip into the membrane, but do not cross it (PubMed:26280335). In contrast, results based on mutagenesis to create N-glycosylation sites indicate that the N-terminus is lumenal (PubMed:12639958, PubMed:30598546, PubMed:30630874). Both studies indicate that the C-terminus is lumenal (PubMed:12639958, PubMed:26280335). UniProt Q9NZ42 1 EQUAL 101 EQUAL Reactome Database ID Release 81 157331 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=157331 Reactome R-HSA-157331 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-157331.1 1 NCSTN Nicastrin NICA_HUMAN Reactome DB_ID: 2534241 UniProt:Q92542 NCSTN NCSTN KIAA0253 UNQ1874/PRO4317 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.SUBUNIT Component of the gamma-secretase complex (PubMed:10993067, PubMed:30598546, PubMed:30630874). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). Interacts with PSEN1 and PSEN2 (PubMed:10993067).TISSUE SPECIFICITY Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).INDUCTION Constitutively expressed in neural cells.PTM N-glycosylated.SIMILARITY Belongs to the nicastrin family. UniProt Q92542 34 EQUAL 709 EQUAL Reactome Database ID Release 81 2534241 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=2534241 Reactome R-HSA-2534241 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-2534241.1 1 Reactome Database ID Release 81 157343 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=157343 Reactome R-HSA-157343 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-157343.2 GENE ONTOLOGY GO:0004190 Reactome Database ID Release 81 157355 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=157355 Reactome Database ID Release 81 9604294 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=9604294 Reactome R-HSA-9604294 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-9604294.1 11518718 Pubmed 2001 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis Saxena, MT Schroeter, EH Mumm, JS Kopan, R J Biol Chem 276:40268-73 15123653 Pubmed 2004 Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function Das, I Craig, Colleen Funahashi, Y Jung, Kwang-Mook Kim, Tae-Wan Byers, Richard Weng, Andrew P Kutok, Jeffery L Aster, JC Kitajewski, J J. Biol. Chem. 279:30771-80 LEFT-TO-RIGHT NICD4 traffics to the nucleus The cytosolic NICD4 translocates to the nucleus. Trafficking of NICD4 to the nucleus is negatively regulated by binding of NICD4 to 14-3-3-zeta (YWHAZ), which happens upon NICD4 phosphorylation by activated AKT1 (Ramakrishnan et al. 2015). Authored: Jassal, B, 2004-12-15 13:08:03 Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 NICD4 NOTCH4(1467-2003) NICD 4 fragment N4ICD Reactome DB_ID: 157945 nucleoplasm GENE ONTOLOGY GO:0005654 1467 EQUAL 2003 EQUAL Reactome Database ID Release 81 157945 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=157945 Reactome R-HSA-157945 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-157945.1 Reactome Database ID Release 81 9604308 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=9604308 Reactome R-HSA-9604308 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-9604308.1 25740432 Pubmed 2015 AKT and 14-3-3 regulate Notch4 nuclear localization Ramakrishnan, Gopalakrishnan Davaakhuu, Gantulga Chung, Wen Cheng Zhu, He Rana, Ajay Filipovic, Aleksandra Green, Andrew R Atfi, Azeddine Pannuti, Antonio Miele, Lucio Tzivion, Guri Sci Rep 5:8782 INHIBITION activeUnit: #Complex11 Reactome Database ID Release 81 9604397 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=9604397 p-4S-NICD4:YWHAZ dimer Reactome DB_ID: 9604390 YWHAZ dimer 14-3-3 zeta dimer Reactome DB_ID: 206751 YWHAZ 14-3-3 zeta Reactome DB_ID: 206099 UniProt:P63104 YWHAZ YWHAZ FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity).SUBUNIT Interacts with CDK16 and BSPRY (By similarity). Interacts with WEE1 (C-terminal). Interacts with SAMSN1 (By similarity). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm (By similarity). Interacts with Thr-phosphorylated ITGB2 (By similarity). Interacts with BCL2L11 (By similarity). Homodimer. Heterodimerizes with YWHAE. Homo- and heterodimerization is inhibited by phosphorylation on Ser-58. Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232 (PubMed:31024343). Interacts with BRAF (PubMed:31024343). Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization. Interacts with GAB2 and TLK2. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1 (PubMed:16959763). Interacts with MEFV (PubMed:27030597).PTM The delta, brain-specific form differs from the zeta form in being phosphorylated (By similarity). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1. Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.SIMILARITY Belongs to the 14-3-3 family.CAUTION Was originally thought to have phospholipase A2 activity. UniProt P63104 1 EQUAL 245 EQUAL Reactome Database ID Release 81 206099 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=206099 Reactome R-HSA-206099 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-206099.1 2 Reactome Database ID Release 81 206751 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=206751 Reactome R-HSA-206751 3 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-206751.3 1 p-4S-NICD4 p-4S-NOTCH4(1467-2003) Reactome DB_ID: 9604329 1495 EQUAL O-phospho-L-serine MOD MOD:00046 1847 EQUAL 1865 EQUAL 1917 EQUAL 1467 EQUAL 2003 EQUAL Reactome Database ID Release 81 9604329 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=9604329 Reactome R-HSA-9604329 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-9604329.1 1 Reactome Database ID Release 81 9604390 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=9604390 Reactome R-HSA-9604390 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-9604390.1 Reactome Database ID Release 81 9013700 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=9013700 Reactome R-HSA-9013700 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-9013700.1 20161710 Pubmed 2010 Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors Aste-Amézaga, Miguel Zhang, Ningyan Lineberger, Janet E Arnold, Beth A Toner, Timothy J Gu, Mingcheng Huang, Lingyi Vitelli, Salvatore Vo, Kim T Haytko, Peter Zhao, Jing Zhang Baleydier, Frederic L'Heureux, S Wang, Hongfang Gordon, Wendy R Thoryk, Elizabeth Andrawes, Marie Blanke Tiyanont, Kittichoat Stegmaier, Kimberly Roti, Giovanni Ross, Kenneth N Franlin, Laura L Wang, Hui Wang, Fubao Chastain, Michael Bett, Andrew J Audoly, Laurent P Aster, JC Blacklow, SC Huber, HE PLoS ONE 5:e9094 10964583 Pubmed 2000 Notch4 and Jagged-1 induce microvessel differentiation of rat brain endothelial cells Uyttendaele, H Closson, V Wu, G Roux, F Weinmaster, G Kitajewski, J Microvasc. Res. 60:91-103 12386158 Pubmed 2002 Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling Lin, Sey-En Oyama, Toshinao Nagase, Takahiro Harigaya, Kenichi Kitagawa, Motoo J. Biol. Chem. 277:50612-20 20804727 Pubmed 2010 Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats Bargo, Sharon Raafat, Ahmed McCurdy, David Amirjazil, Idean Shu, Youmin Traicoff, June Plant, Joshua Vonderhaar, Barbara K Callahan, Robert Biochem. Biophys. Res. Commun. 400:606-12 24667410 Pubmed 2014 Notch4 reveals a novel mechanism regulating Notch signal transduction James, A C Szot, J O Iyer, K Major, J A Pursglove, S E Chapman, G Dunwoodie, S L Biochim. Biophys. Acta 1843:1272-84 GENE ONTOLOGY GO:0007219 NOTCH4 Intracellular Domain Regulates Transcription In the nucleus, NOTCH4 intracellular domain fragment (NICD4) binds transcription factors RBPJ (CSL) and mastermind family members (MAML1, MAML2 or MAML3) to form the NOTCH4 co-activator complex (Lin et al. 2002). The NOTCH4 coactivator complex stimulates transcription of well-established NOTCH targets HES1, HES5, HEY1 and HEY2 in a cellular context-dependent manner (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Bargo et al. 2010). NOTCH4 also stimulates transcription of the FLT4 (VEGFR3) gene, encoding vascular endothelial growth factor receptor-3 (Shawber et al. 2007) and ACTA2 gene, encoding smooth muscle alpha actin (Tang et al. 2008).<br><br>NICD4 inhibits TGF-beta-induced SMAD-mediated transcription via binding of NICD4 to TGF-beta activated SMAD3 (Sun et al. 2005, Grabias and Konstantopoulos 2013). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 LEFT-TO-RIGHT NICD4 binds RBPJ and MAML in the nucleus In the nucleus, NICD4 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind) proteins MAML1, MAML2 or MAML3 (possibly also MAMLD1). NICD4:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (Lin et al. 2002).<br><br>Besides NICD4, RBPJ and MAML, NOTCH4 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD4, it is not shown here. More details are available in the pathway Signaling by NOTCH1.<br><br>NOTCH4 does not alter DNA binding specificity of RBPJ (Del Bianco et al. 2010). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 RBPJ Recombining binding protein suppressor of hairless SUH_HUMAN CBF1 Reactome DB_ID: 3008668 UniProt:Q06330 RBPJ RBPJ IGKJRB IGKJRB1 RBPJK RBPSUH FUNCTION Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA (PubMed:21991380). Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen) (PubMed:23303788). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits (By similarity).SUBUNIT Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIR1. Interacts with EP300, MAML1 and PTF1A. Interacts with Epstein-Barr virus EBNA2, EBNA3, EBNA4 and EBNA6. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5 (PubMed:23303788). Interacts with BEND6 (via BEN domain). Interacts with NKAPL (By similarity). Interacts with ZMIZ1. Interacts with RBM15 (By similarity).SIMILARITY Belongs to the Su(H) family.CAUTION Despite some similarity with the 'phage' integrase family, it has no recombinase activity. UniProt Q06330 1 EQUAL 500 EQUAL Reactome Database ID Release 81 3008668 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=3008668 Reactome R-HSA-3008668 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-3008668.1 Converted from EntitySet in Reactome MAML Reactome DB_ID: 212357 MAML1 Reactome DB_ID: 212416 UniProt:Q92585 MAML1 MAML1 KIAA0200 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.SUBUNIT Interacts (via N-terminus) with NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (via ankyrin repeat region). Interacts (via N-terminus) with p53 (via DNA-binding region). Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1. Also binds CREBBP/CBP and CDK8.Forms a complex with PRAG1, NOTCH1 and MAML1, in a MAML1-dependent manner (By similarity).TISSUE SPECIFICITY Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.DOMAIN The C-terminal region is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q92585 1 EQUAL 1016 EQUAL Reactome Database ID Release 81 212416 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=212416 Reactome R-HSA-212416 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-212416.1 MAML2 Reactome DB_ID: 212353 UniProt:Q8IZL2 MAML2 MAML2 KIAA1819 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.TISSUE SPECIFICITY Widely expressed with high levels detected in placenta, salivary gland and skeletal muscle.DOMAIN The C-terminal domain is required for transcriptional activation.DISEASE A chromosomal aberration involving MAML2 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with CRTC1. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas.SIMILARITY Belongs to the mastermind family. UniProt Q8IZL2 1 EQUAL 1156 EQUAL Reactome Database ID Release 81 212353 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=212353 Reactome R-HSA-212353 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-212353.1 MAML3 MAML3_HUMAN Reactome DB_ID: 349689 UniProt:Q96JK9 MAML3 MAML3 KIAA1816 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.DOMAIN The C-terminal domain is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q96JK9 1 EQUAL 1134 EQUAL Reactome Database ID Release 81 349689 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=349689 Reactome R-HSA-349689 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-349689.1 MAMLD1 MAMD1_HUMAN Reactome DB_ID: 349692 UniProt:Q13495 MAMLD1 MAMLD1 CG1 CXorf6 FUNCTION Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.TISSUE SPECIFICITY Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.INDUCTION By NR5A1.SIMILARITY Belongs to the mastermind family. UniProt Q13495 1 EQUAL 774 EQUAL Reactome Database ID Release 81 349692 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=349692 Reactome R-HSA-349692 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-349692.1 Reactome Database ID Release 81 212357 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=212357 Reactome R-HSA-212357 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-212357.2 NOTCH4 coactivator complex Reactome DB_ID: 9013697 1 1 1 Reactome Database ID Release 81 9013697 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=9013697 Reactome R-HSA-9013697 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-9013697.1 Reactome Database ID Release 81 9013693 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=9013693 Reactome R-HSA-9013693 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-9013693.1 21124806 Pubmed 2010 Notch and MAML-1 complexation do not detectably alter the DNA binding specificity of the transcription factor CSL Del Bianco, Cristina Vedenko, Anastasia Choi, SH Berger, Michael F Shokri, Leila Bulyk, Martha L Blacklow, SC PLoS ONE 5:e15034 LEFT-TO-RIGHT HES1 gene expression is stimulated by NOTCH4 NOTCH4 expression correlates with increased HES1 gene transcription in different cell types (Raafat et al. 2004, Lai et al. 2013, Simoes et al. 2015). A recombinant human NICD4 stimulates transcription from the recombinant human HES1-luciferase reporter construct (Raafat et al. 2004). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 HES1 gene Reactome DB_ID: 2197548 ENSEMBL:ENSG00000114315 HES1 HES1 BHLHB39 HL HRY ENSEMBL ENSG00000114315 Reactome Database ID Release 81 2197548 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=2197548 Reactome R-HSA-2197548 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-2197548.2 HES1 Hairy and enhancer of split 1 Transcription factor HES-1 Reactome DB_ID: 210825 UniProt:Q14469 HES1 HES1 BHLHB39 HL HRY FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. May act as a negative regulator of myogenesis by inhibiting the functions of MYOD1 and ASH1. Binds DNA on N-box motifs: 5'-CACNAG-3' with high affinity and on E-box motifs: 5'-CANNTG-3' with low affinity (By similarity). May play a role in a functional FA core complex response to DNA cross-link damage, being required for the stability and nuclear localization of FA core complex proteins, as well as for FANCD2 monoubiquitination in response to DNA damage.SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts (via WPRW motif) with TLE1, and more weakly with TLE2. Interacts with HES6 (By similarity). Interacts with SIRT1. Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL, but not of FANCC, nor FANCE.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.DOMAIN The bHLH, as well as cooperation between the central Orange domain and the C-terminal WRPW motif, is required for transcriptional repressor activity. UniProt Q14469 1 EQUAL 280 EQUAL Reactome Database ID Release 81 210825 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=210825 Reactome R-HSA-210825 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-210825.1 Reactome Database ID Release 81 9013711 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=9013711 Reactome R-HSA-9013711 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-9013711.1 23237809 Pubmed 2013 Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes Lai, Peng-Yeh Tsai, Chong-Bin Tseng, Min-Jen Biochem. Biophys. Res. Commun. 430:1132-9 15531924 Pubmed 2004 Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh) Raafat, Ahmed Bargo, Sharon Anver, Miriam R Callahan, Robert Oncogene 23:9401-7 GENE ONTOLOGY GO:0045893 ACTIVATION Reactome Database ID Release 81 9604435 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=9604435 LEFT-TO-RIGHT HES5 gene expression is stimulated by NOTCH4 The NOTCH4 co-activator complex, composed of NICD4 (NOTCH4 intracellular domain), RBPJ (CSL) and one of mastermind proteins, MAML1, MAML2 or MAML3, stimulates transcription from the HES5 gene promoter. The highest level of transcriptional activation of HES5 by NOTCH4 is seen when MAML2 is overexpressed, compared to the other two MAML proteins (Lin et al. 2002). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 HES5 gene Reactome DB_ID: 2197557 ENSEMBL:ENSG00000197921 HES5 HES5 BHLHB38 ENSEMBL ENSG00000197921 Reactome Database ID Release 81 2197557 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=2197557 Reactome R-HSA-2197557 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-2197557.2 HES5 Transcription factor HES-5 Class B basic helix-loop-helix protein 38 Hairy and enhancer of split 5 BHLHB38 Reactome DB_ID: 1606739 UniProt:Q5TA89 HES5 HES5 BHLHB38 FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.TISSUE SPECIFICITY Expressed in fetal heart and brain tumors.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins. UniProt Q5TA89 1 EQUAL 166 EQUAL Reactome Database ID Release 81 1606739 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=1606739 Reactome R-HSA-1606739 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-1606739.1 Reactome Database ID Release 81 9604446 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=9604446 Reactome R-HSA-9604446 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-9604446.1 ACTIVATION Reactome Database ID Release 81 9604457 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=9604457 LEFT-TO-RIGHT NOTCH4 binds FLT4 gene promoter The NOTCH4 coactivator complex, composed of NICD4 (NOTCH4 intracellular domain fragment), RBPJ (CSL) and one of mastermind proteins, MAML1, MAML2 or MAML3, binds to CSL response elements in the promoter of the FLT4 (VEGFR3) gene, encoding Vascular endothelial growth factor receptor-3 (Shawber et al. 2007). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 FLT4 gene VEGFR3 gene Reactome DB_ID: 9604466 ENSEMBL:ENSG00000037280 FLT4 FLT4 VEGFR3 ENSEMBL ENSG00000037280 Reactome Database ID Release 81 9604466 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=9604466 Reactome R-HSA-9604466 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-9604466.1 NOTCH4 coactivator complex:FLT4 gene Reactome DB_ID: 9604465 1 1 Reactome Database ID Release 81 9604465 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=9604465 Reactome R-HSA-9604465 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-9604465.1 Reactome Database ID Release 81 9604451 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=9604451 Reactome R-HSA-9604451 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-9604451.1 LEFT-TO-RIGHT FLT4 gene expression is stimulated by NOTCH4 Transcription of the FLT4 (VEGFR3) gene, encoding Vascular endothelial growth factor receptor-3, is directly stimulated by the NOTCH4 co-activator complex (Shawber et al. 2007). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 FLT4 VEGFR3 Reactome DB_ID: 195359 UniProt:P35916 FLT4 FLT4 VEGFR3 FUNCTION Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51.SUBUNIT Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1.TISSUE SPECIFICITY Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.DOMAIN The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding (PubMed:23878260). The fourth and fifth Ig-like C2-type domains are sufficient for homodimerization (PubMed:23878260). The fifth and seventh Ig-like C2-type domains are required for autophosphorylation and further activation (PubMed:23878260).PTM Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H(2)O(2) is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337.DISEASE Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. UniProt P35916 25 EQUAL 1363 EQUAL Reactome Database ID Release 81 195359 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=195359 Reactome R-HSA-195359 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-195359.2 Reactome Database ID Release 81 9604471 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=9604471 Reactome R-HSA-9604471 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-9604471.1 ACTIVATION activeUnit: #Complex12 Reactome Database ID Release 81 9604473 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=9604473 LEFT-TO-RIGHT HEY1 gene expression is stimulated by NOTCH4 Increased NOTCH4 levels correlate with increased HEY1 gene expression (Tsunematsu et al. 2004, Simoes et al. 2015, Bonyadi Rad et al. 2016, Fukusumi et al. 2018). NOTCH4-mediated upregulation of HEY1 in head and neck squamous cell carcinoma (HNSCC) is associated with epithelial-to-mesenchymal transition (EMT) phenotype (Fukusumi et al. 2018). In melanoma, however, HEY1 and HEY2 expression downstream of NOTCH4 is associated with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 HEY1 gene Reactome DB_ID: 4396358 ENSEMBL:ENSG00000164683 HEY1 HEY1 BHLHB31 CHF2 HERP2 HESR1 HRT1 ENSEMBL ENSG00000164683 Reactome Database ID Release 81 4396358 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=4396358 Reactome R-HSA-4396358 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-4396358.2 HEY1 Hairy/enhancer-of-split related with YRPW motif protein 1 Cardiovascular helix-loop-helix factor 2 Class B basic helix-loop-helix protein 31 HES-related repressor protein 1 Hairy and enhancer of split-related protein 1 Hairy-related transcription factor 1 BHLHB31 CHF2 HERP2 HESR1 HRT1 Reactome DB_ID: 1606744 UniProt:Q9Y5J3 HEY1 HEY1 BHLHB31 CHF2 HERP2 HESR1 HRT1 FUNCTION Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (PubMed:11095750). Downstream effector of Notch signaling required for cardiovascular development. Specifically required for the Notch-induced endocardial epithelial to mesenchymal transition, which is itself criticial for cardiac valve and septum development. May be required in conjunction with HEY2 to specify arterial cell fate or identity. Promotes maintenance of neuronal precursor cells and glial versus neuronal fate specification. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6 and by the neuronal bHLH factors ASCL1/MASH1 and NEUROD4/MATH3 (PubMed:15485867). Involved in the regulation of liver cancer cells self-renewal (PubMed:25985737).SUBUNIT Self-associates. Interacts with HES1 and HEYL. Interacts with HDAC1, NCOR1 and SIN3A. Interacts with GATA4 and GATA6. Interacts with CCDC89/BOIP.TISSUE SPECIFICITY Expressed in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs.SIMILARITY Belongs to the HEY family. UniProt Q9Y5J3 1 EQUAL 304 EQUAL Reactome Database ID Release 81 1606744 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=1606744 Reactome R-HSA-1606744 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-1606744.1 Reactome Database ID Release 81 9604550 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=9604550 Reactome R-HSA-9604550 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-9604550.1 14672936 Pubmed 2004 Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development Tsunematsu, Ryosuke Nakayama, Keiko Oike, Yuichi Nishiyama, Masaaki Ishida, Noriko Hatakeyama, Shigetsugu Bessho, Yasumasa Kageyama, Ryoichiro Suda, Toshio Nakayama, Keiichi I J. Biol. Chem. 279:9417-23 26801977 Pubmed 2016 Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors Bonyadi Rad, Ehsan Hammerlindl, Heinz Wels, Christian Popper, Ulrich Ravindran Menon, Dinoop Breiteneder, Heimo Kitzwoegerer, Melitta Hafner, Christine Herlyn, Meenhard Bergler, Helmut Schaider, Helmut Cancer Res. 76:1690-7 29146722 Pubmed 2018 The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma Fukusumi, Takahito Guo, Theresa W Sakai, Akihiro Ando, Mizuo Ren, Shuling Haft, Sunny Liu, Chao Amornphimoltham, Panomwat Gutkind, J Silvio Califano, Joseph A Clin. Cancer Res. 24:619-633 ACTIVATION Reactome Database ID Release 81 9604598 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=9604598 LEFT-TO-RIGHT HEY2 gene expression is stimulated by NOTCH4 Increased NOTCH4 levels and activity correlate with increased HEY2 gene expression (Bargo et al. 2010, Simoes et al. 2015, Bonyadi Rad et al. 2016). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 HEY2 gene Reactome DB_ID: 4396355 ENSEMBL:ENSG00000135547 HEY2 HEY2 BHLHB32 CHF1 GRL HERP HERP1 HRT2 ENSEMBL ENSG00000135547 Reactome Database ID Release 81 4396355 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=4396355 Reactome R-HSA-4396355 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-4396355.2 GRL HEY2 Hairy/enhancer-of-split related with YRPW motif protein 2 Cardiovascular helix-loop-helix factor 1 Class B basic helix-loop-helix protein 32 HES-related repressor protein 2 Hairy and enhancer of split-related protein 2 Hairy-related transcription factor 2 BHLHB32 CHF1 HERP HERP1 HRT2 Reactome DB_ID: 1606745 UniProt:Q9UBP5 HEY2 HEY2 BHLHB32 CHF1 GRL HERP HERP1 HRT2 FUNCTION Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.SUBUNIT May self-associate (By similarity). Interacts with GATA4, HES1 and HEYL (By similarity). Interacts with HDAC1, NCOR1 and SIN3A (By similarity). Interacts with ARNT and GATA6.SIMILARITY Belongs to the HEY family. UniProt Q9UBP5 1 EQUAL 337 EQUAL Reactome Database ID Release 81 1606745 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=1606745 Reactome R-HSA-1606745 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-1606745.1 Reactome Database ID Release 81 9604553 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=9604553 Reactome R-HSA-9604553 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-9604553.1 ACTIVATION Reactome Database ID Release 81 9604596 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=9604596 LEFT-TO-RIGHT ACTA2 gene expression is stimulated by NOTCH1, NOTCH2 and NOTCH4 ACTA2 gene, encoding smooth muscle alpha actin, possesses several RBPJ (CSL) response elements in its promoter region. Transcription of ACTA2 is positively regulated by NOTCH1, NOTCH2 and NOTCH4 (Tang et al. 2008). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 ACTA2 gene Reactome DB_ID: 8957900 ENSEMBL:ENSG00000107796 ACTA2 ACTA2 ACTSA ACTVS GIG46 ENSEMBL ENSG00000107796 Reactome Database ID Release 81 8957900 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=8957900 Reactome R-HSA-8957900 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-8957900.1 ACTA2 Actin, aortic smooth muscle ACTA_HUMAN Reactome DB_ID: 445792 UniProt:P62736 ACTA2 ACTA2 ACTSA ACTVS GIG46 FUNCTION Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.SUBUNIT Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to 4 others.INDUCTION Up-regulated in response to enterovirus 71 (EV71) infection.PTM Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or MICAL3) to form methionine sulfoxide promotes actin filament depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form. The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promotes actin repolymerization.PTM Monomethylation at Lys-86 (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes. Demethylation by ALKBH4 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration.PTM Methylated at His-75 by SETD3.PTM (Microbial infection) Monomeric actin is cross-linked by V.cholerae toxins RtxA and VgrG1 in case of infection: bacterial toxins mediate the cross-link between Lys-52 of one monomer and Glu-272 of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148).DISEASE ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, premature onset coronary artery disease (CAD), premature ischemic strokes and Moyamoya disease.MISCELLANEOUS In vertebrates 3 main groups of actin isoforms, alpha, beta and gamma have been identified. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton and as mediators of internal cell motility.SIMILARITY Belongs to the actin family. UniProt P62736 3 EQUAL 377 EQUAL Reactome Database ID Release 81 445792 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=445792 Reactome R-HSA-445792 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-445792.1 Reactome Database ID Release 81 9604664 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=9604664 Reactome R-HSA-9604664 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-9604664.1 18239137 Pubmed 2008 Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site Tang, Yuefeng Urs, Sumithra Liaw, Lucy Circ. Res. 102:661-8 ACTIVATION Reactome Database ID Release 81 9604662 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=9604662 Converted from EntitySet in Reactome NOTCH1,NOTCH2,NOTCH4 coactivator complex Reactome DB_ID: 9604665 NOTCH1 Coactivator Complex Reactome DB_ID: 1604462 Converted from EntitySet in Reactome PCAF Reactome DB_ID: 350078 PCAF KAT2B PCAF_HUMAN Histone acetyltransferase PCAF Reactome DB_ID: 352430 UniProt:Q92831 KAT2B KAT2B PCAF FUNCTION Functions as a histone acetyltransferase (HAT) to promote transcriptional activation (PubMed:8945521). Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles (PubMed:8945521). Also acetylates non-histone proteins, such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K and TBX5 (PubMed:9707565, PubMed:10675335, PubMed:23001180, PubMed:27796307, PubMed:23932781, PubMed:26867678, PubMed:29174768). Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A (PubMed:8684459). Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acetylates RRP9/U3-55K, a core subunit of the U3 snoRNP complex, impairing pre-rRNA processing (PubMed:26867678). Acetylates MAPRE1/EB1, promoting dynamic kinetochore-microtubule interactions in early mitosis (PubMed:23001180). Also acetylates spermidine (PubMed:27389534).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.ACTIVITY REGULATION Activated in vitro by very low concentrations of spermidine, but inhibited at spermidine concentrations higher than 4 uM. The activating effect of low spermidine concentrations may be mediated by N(8)-acetylspermidine produced by KAT2B/P/CAF itself acting as a positive feedback loop.SUBUNIT Interacts with SIRT1. Interacts (unsumoylated form) with NR2C1; the interaction promotes transactivation activity (By similarity). Interacts with EP300, CREBBP and DDX17. Interacts with NCOA1 and NCOA3. Component of a large chromatin remodeling complex, at least composed of MYSM1, KAT2B/PCAF, RBM10 and KIF11/TRIP5. Interacts with NR2C2 (hypophosphorylated and unsumoylated form); the interaction promotes the transactivation activity of NR2C2. Interacts with KLF1; the interaction does not acetylate KLF1 and there is no enhancement of its transactivational activity. Interacts with NFE4. Interacts with MECOM. Interacts with E2F1; the interaction acetylates E2F1 augmenting its DNA-binding and transcriptional activity. Interacts with NPAS2, ARNTL/BMAL1 and CLOCK. Interacts with BCAS3. Interacts with CEBPB (PubMed:17301242). Interacts with NR4A3 (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Interacts with RB1; this interaction leads to RB1 acetylation (By similarity).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax.TISSUE SPECIFICITY Ubiquitously expressed but most abundant in heart and skeletal muscle. Also expressed in the skin, in keratinocytes (at protein level) (PubMed:20940255).DEVELOPMENTAL STAGE Up-regulated during keratinocyte differentiation (at protein level).DOMAIN (Microbial infection) The bromodomain mediates binding to HIV-1 Tat.DISEASE Defects in KAT2B has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily. UniProt Q92831 1 EQUAL 832 EQUAL Reactome Database ID Release 81 352430 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=352430 Reactome R-HSA-352430 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-352430.1 GCN5 KAT2A Histone acetyltransferase KAT2A KAT2A_HUMAN Reactome DB_ID: 3006516 UniProt:Q92830 KAT2A KAT2A GCN5 GCN5L2 FUNCTION Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase or succinyltransferase, depending on the context (PubMed:29211711). Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes (PubMed:29211711). Succinylation of histones gives a specific tag for epigenetic transcription activation (PubMed:29211711). Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation (PubMed:29211711). In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase (PubMed:17301242, PubMed:19103755, PubMed:29211711). Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles (PubMed:17301242, PubMed:19103755). Acetylation of histones gives a specific tag for epigenetic transcription activation (PubMed:17301242, PubMed:19103755, PubMed:29211711). Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes (PubMed:29973595, PubMed:31527837). Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling (By similarity). Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression (By similarity). Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac) (By similarity). Regulates embryonic stem cell (ESC) pluripotency and differentiation (By similarity). Also acetylates non-histone proteins, such as CEBPB, PLK4 and TBX5 (PubMed:17301242, PubMed:27796307, PubMed:29174768). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.SUBUNIT Homooligomer; may form a tetramer of homodimers (PubMed:30109122). Interacts with EP300, CREBBP and ADA2. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TAF3, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, KAT2A/GCN5L2, TAF10 and TRRAP (PubMed:10373431, PubMed:10611234, PubMed:11438666). Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, KAT2A, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:18206972). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). In the complex, it probably interacts directly with KAT14, MBIP and WDR5 (PubMed:19103755). Interacts with PML (By similarity). Interacts with CEBPB (PubMed:17301242). Interacts with TACC1, TACC2 and TACC3 (PubMed:14767476). Interacts with RELA (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Associates with the 2-oxoglutarate dehydrogenase complex (PubMed:29211711). Interacts with XPC; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837). Interacts with ERCC3/XPB; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:30894545).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.TISSUE SPECIFICITY Expressed in all tissues tested, with most abundant expression in ovary.DOMAIN Loop3 is required for substrate specificity and adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Tyr-645 has an important role in the selective binding of succinyl-CoA over acetyl-CoA.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily.CAUTION According to a report, has weak protein acyltransferase activity compared to protein acetyltransferase activity (PubMed:27377381). These conclusions are however not supported by subsequent studies (PubMed:29211711, PubMed:31542297). UniProt Q92830 1 EQUAL 837 EQUAL Reactome Database ID Release 81 3006516 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=3006516 Reactome R-HSA-3006516 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-3006516.1 Reactome Database ID Release 81 350078 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=350078 Reactome R-HSA-350078 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-350078.1 1 p300 EP300 Histone acetyltransferase p300 EP300_HUMAN KAT3B Reactome DB_ID: 381325 UniProt:Q09472 EP300 EP300 P300 FUNCTION Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRMT1 or SIRT2 (PubMed:12929931, PubMed:16762839, PubMed:18722353). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Following DNA damage, forms a stress-responsive p53/TP53 coactivator complex with JMY which mediates p53/TP53 acetylation, thereby increasing p53/TP53-dependent transcription and apoptosis (PubMed:11511361, PubMed:15448695). Promotes chromatin acetylation in heat shock responsive HSP genes during the heat shock response (HSR), thereby stimulating HSR transcription (PubMed:18451878). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acetylates 'Lys-247' of EGR2 (By similarity). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degradation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). Acetylates GABPB1, impairing GABPB1 heterotetramerization and activity (By similarity). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097). Acetylates RXRA and RXRG (PubMed:17761950). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA), 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), lactoyl-CoA or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation, 2-hydroxyisobutyrylation, lactylation or propionylation, respectively (PubMed:17267393, PubMed:25818647, PubMed:29775581, PubMed:31645732). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (2E)-butenoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Catalyzes histone lactylation in macrophages by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription (PubMed:31645732). Acts as a protein-lysine 2-hydroxyisobutyryltransferase; regulates glycolysis by mediating 2-hydroxyisobutyrylation of glycolytic enzymes (PubMed:29775581). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein.SUBUNIT Interacts with HIF1A; the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:9887100, PubMed:11959990). Probably part of a complex with HIF1A and CREBBP (PubMed:8917528). Interacts (via N-terminus) with TFAP2A (via N-terminus); the interaction requires CITED2 (PubMed:12586840). Interacts (via CH1 domain) with CITED2 (via C-terminus) (PubMed:12586840, PubMed:12778114). Interacts with CITED1 (unphosphorylated form preferentially and via C-terminus) (PubMed:10722728, PubMed:16864582). Interacts with ESR1; the interaction is estrogen-dependent and enhanced by CITED1 (PubMed:11581164). Interacts with HIPK2 (By similarity). Interacts with DTX1, EID1, ELF3, FEN1, LEF1, NCOA1, NCOA6, NR3C1, PCAF, PELP1, PRDM6, SP1, SP3, SPIB, SRY, TCF7L2, DDX5, DDX17, SATB1, SRCAP and TRERF1 (PubMed:11073989, PubMed:11073990, PubMed:10823961, PubMed:11349124, PubMed:11430825, PubMed:11481323, PubMed:11564735, PubMed:11581372, PubMed:11864910, PubMed:12446687, PubMed:12527917, PubMed:12837748, PubMed:14605447, PubMed:15075319, PubMed:15297880, PubMed:16478997, PubMed:8684459, PubMed:17226766, PubMed:9590696). Interacts with JMY, the complex activates p53/TP53 transcriptional activity (PubMed:10518217, PubMed:11511361). Interacts with TTC5/STRAP; the interaction facilitates the association between JMY and p300/EP300 cofactors (PubMed:11511361). Interacts with p53/TP53; the interation is facilitated by TTC5/STRAP (PubMed:15186775, PubMed:15448695, PubMed:19217391). Forms a complex with TTC5/STRAP and HSF1; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (PubMed:18451878). Part of a complex containing CARM1 and NCOA2/GRIP1 (PubMed:11701890, PubMed:11997499, PubMed:15731352). Interacts with ING4 and this interaction may be indirect (PubMed:12750254). Interacts with ING5 (PubMed:12750254). Interacts with the C-terminal region of CITED4 (PubMed:11744733). Non-sumoylated EP300 preferentially interacts with SENP3 (PubMed:19680224). Interacts with SS18L1/CREST (PubMed:14716005). Interacts with ALX1 (via homeobox domain) (PubMed:12929931). Interacts with NEUROD1; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with TCF3 (PubMed:14752053). Interacts (via CREB-binding domain) with MYOCD (via C-terminus) (By similarity). Interacts with ROCK2 and PPARG (PubMed:11518699, PubMed:16574662). Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). Interacts with IRF1 and this interaction enhances acetylation of p53/TP53 and stimulation of its activity (PubMed:15509808). Interacts with FOXO1; the interaction acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Interacts with ALKBH4 and DDIT3/CHOP (PubMed:17872950, PubMed:23145062). Interacts with KLF15 (PubMed:23999430). Interacts with CEBPB and RORA (PubMed:9862959). Interacts with NPAS2, ARNTL/BMAL1 and CLOCK (PubMed:14645221). Interacts with SIRT2 isoform 1, isoform 2 and isoform 5 (PubMed:24177535). Interacts with MTA1 (PubMed:16617102). Interacts with HDAC4 and HDAC5 in the presence of TFAP2C (PubMed:24413532). Interacts with TRIP4 (PubMed:25219498). Directly interacts with ZBTB49; this interaction leads to synergistic transactivation of CDKN1A (PubMed:25245946). Interacts with NR4A3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with ZBTB48/TZAP (PubMed:24382891). Interacts with STAT1; the interaction is enhanced upon IFN-gamma stimulation (PubMed:26479788). Interacts with HNRNPU (via C-terminus); this interaction enhances DNA-binding of HNRNPU to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with BCL11B (PubMed:27959755, PubMed:16809611). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Interacts with NUPR1; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591). Interacts with RXRA; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). Interacts with RB1 (By similarity). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295). Interacts with SOX9 (PubMed:12732631). Interacts with ATF4; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination (PubMed:16219772). Interacts with KAT5; promoting KAT5 autoacetylation (PubMed:24835996).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction stimulates the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-protein complex.SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 proteins Tax, p30II and HBZ.DOMAIN The CRD1 domain (cell cycle regulatory domain 1) mediates transcriptional repression of a subset of p300 responsive genes; it can be de-repressed by CDKN1A/p21WAF1 at least at some promoters. It conatins sumoylation and acetylation sites and the same lysine residues may be targeted for the respective modifications. It is proposed that deacetylation by SIRT1 allows sumoylation leading to suppressed activity.PTM Acetylated on Lys at up to 17 positions by intermolecular autocatalysis. Deacetylated in the transcriptional repression domain (CRD1) by SIRT1, preferentially at Lys-1020. Deacetylated by SIRT2, preferentially at Lys-418, Lys-423, Lys-1542, Lys-1546, Lys-1549, Lys-1699, Lys-1704 and Lys-1707.PTM Citrullinated at Arg-2142 by PADI4, which impairs methylation by CARM1 and promotes interaction with NCOA2/GRIP1.PTM Methylated at Arg-580 and Arg-604 in the KIX domain by CARM1, which blocks association with CREB, inhibits CREB signaling and activates apoptotic response. Also methylated at Arg-2142 by CARM1, which impairs interaction with NCOA2/GRIP1.PTM Sumoylated; sumoylation in the transcriptional repression domain (CRD1) mediates transcriptional repression. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.PTM Probable target of ubiquitination by FBXO3, leading to rapid proteasome-dependent degradation.PTM Phosphorylated by HIPK2 in a RUNX1-dependent manner. This phosphorylation that activates EP300 happens when RUNX1 is associated with DNA and CBFB. Phosphorylated by ROCK2 and this enhances its activity. Phosphorylation at Ser-89 by AMPK reduces interaction with nuclear receptors, such as PPARG.DISEASE Defects in EP300 may play a role in epithelial cancer.DISEASE Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. UniProt Q09472 2 EQUAL 2414 EQUAL Reactome Database ID Release 81 381325 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=381325 Reactome R-HSA-381325 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-381325.1 1 NICD1:RBPJ:SNW1 Reactome DB_ID: 1604460 NICD1 NOTCH1(1754-2555) NICD 1 fragment NOTCH1 intracellular domain N1ICD Reactome DB_ID: 157939 UniProt:P46531 NOTCH1 NOTCH1 TAN1 FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. 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. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, PubMed:12370315). The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164). The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339). Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity. Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1 (By similarity). Interacts (via NICD domain) with PRAG1 (By similarity). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546). Interacts with ZFP64 (By similarity).TISSUE SPECIFICITY In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.DOMAIN Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.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 (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).PTM Phosphorylated.PTM O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).PTM Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).PTM Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).SIMILARITY Belongs to the NOTCH family. UniProt P46531 1754 EQUAL 2555 EQUAL Reactome Database ID Release 81 157939 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=157939 Reactome R-HSA-157939 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-157939.1 1 1 SNW1 SKIP SNW domain-containing protein SNW1_HUMAN Reactome DB_ID: 351663 UniProt:Q13573 SNW1 SNW1 SKIIP SKIP FUNCTION Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Is required in the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. Is proposed to recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD.FUNCTION (Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter.FUNCTION (Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters.SUBUNIT Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs). Interacts with SKI, SMAD2,SMAD3, RBPJ, RB1, PABPN1, MAGEA1, SIRT1, FOXN3, U2AF2, DAXX and ATP1B4. Interacts with PPIL1 (PubMed:16595688, PubMed:20007319, PubMed:20368803, PubMed:33220177). Interacts with VDR and RXRA; preferentially associates with VDR:RXRA heterodimers (PubMed:9632709, PubMed:12529369). Interacts with NCOR2 (PubMed:10644367). Interacts with MAML1 (PubMed:21245387). Interacts with NOTCH1 NICD; the interaction involves multimerized NOTCH1 NICD (PubMed:21245387). Forms a complex with NOTCH1 NICD and MAML1; the association is dissociated by RBPJ (PubMed:21245387). Associates with positive transcription elongation factor b (P-TEFb) (PubMed:15905409). Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN (PubMed:18794151).SUBUNIT (Microbial infection) Interacts with human papillomavirus type-16 (HPV16) E7 protein.SUBUNIT (Microbial infection) Interacts with EBV EBNA2; EBNA2 competes with NCOR2 for interaction with SNW1.SIMILARITY Belongs to the SNW family. UniProt Q13573 2 EQUAL 536 EQUAL Reactome Database ID Release 81 351663 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=351663 Reactome R-HSA-351663 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-351663.1 1 Reactome Database ID Release 81 1604460 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=1604460 Reactome R-HSA-1604460 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-1604460.1 1 KAT3A CREBBP CREB-binding protein CBP_HUMAN Reactome DB_ID: 193545 UniProt:Q92793 CREBBP CREBBP CBP FUNCTION Acetylates histones, giving a specific tag for transcriptional activation (PubMed:24616510). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:9707565, PubMed:24207024, PubMed:28790157, PubMed:30540930). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).SUBUNIT Found in a complex containing NCOA2; NCOA3; IKKA; IKKB and IKBKG. Probably part of a complex with HIF1A and EP300. Interacts with GATA1; the interaction results in acetylation and enhancement of transcriptional activity of GATA1. Interacts with MAF AND ZCCHC12. Interacts with DAXX; the interaction is dependent on CBP sumoylation and results in suppression of the transcriptional activity via recruitment of HDAC2 to DAXX (By similarity). Interacts with phosphorylated CREB1. Interacts with CITED4 (C-terminal region). Interacts (via the TAZ-type 1 domain) with HIF1A. Interacts with SRCAP, CARM1, ELF3, MLLT7/FOXO4, N4BP2, NCOA1, NCOA3, NCOA6, PCAF, DDX5, DDX17, PELP1, PML, SMAD1, SMAD2, SMAD3, SPIB and TRERF1. Interacts with KLF1; the interaction results in acetylation of KLF1 and enhancement of its transcriptional activity. Interacts with MTDH. Interacts with NFATC4. Interacts with MAFG; the interaction acetylates MAFG in the basic region and stimulates NFE2 transcriptional activity through increasing its DNA-binding activity. Interacts with IRF2; the interaction acetylates IRF2 and regulates its activity on the H4 promoter. Interacts with IRF3 (when phosphorylated); forming the dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I interferon genes (PubMed:27302953). Interacts (via N-terminus) with SS18L1/CREST (via C-terminus). Interacts with MECOM. Interacts with CITED1 (via C-terminus). Interacts with FOXO1; the interaction acetylates FOXO1 and inhibits its transcriptional activity. Interacts with NPAS2, CLOCK and ARNTL/BMAL1. Interacts with ASF1A and ASF1B; this promotes histone acetylation. Interacts with acetylated TP53/p53 and with the acetylated histones H3 and H4. Interacts (via transactivation domain and C-terminus) with PCNA; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with DHX9 (via N-terminus); this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation (PubMed:9323138). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Forms a complex with KMT2A and CREB1 (PubMed:23651431). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax, p30II and HBZ.SUBUNIT (Microbial infection) Interacts with human herpes virus 8/HHV-8 protein vIRF-1; this interaction inhibits CREBBP binding to IRF3.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.DOMAIN The KIX domain mediates binding to HIV-1 Tat.PTM Methylation of the KIX domain by CARM1 blocks association with CREB. This results in the blockade of CREB signaling, and in activation of apoptotic response (By similarity).PTM Phosphorylated by CHUK/IKKA at Ser-1382 and Ser-1386; these phosphorylations promote cell growth by switching the binding preference of CREBBP from TP53 to NF-kappa-B.PTM Sumoylation negatively regulates transcriptional activity via the recruitment of DAAX.PTM Autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53.DISEASE Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. UniProt Q92793 1 EQUAL 2442 EQUAL Reactome Database ID Release 81 193545 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=193545 Reactome R-HSA-193545 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-193545.1 1 1 Reactome Database ID Release 81 1604462 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=1604462 Reactome R-HSA-1604462 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-1604462.1 NOTCH2 Coactivator Complex Reactome DB_ID: 2127289 1 1 NICD2 NOTCH2(1697-2471) NICD 2 fragment N2ICD Reactome DB_ID: 157942 UniProt:Q04721 NOTCH2 NOTCH2 FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. 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 (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an 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 NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components (PubMed:29149593). Interacts with MINAR1; this interaction increases MINAR1 stability and function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner (PubMed:29856954). Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519).TISSUE SPECIFICITY Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.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 (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC) (By similarity). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (By similarity). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).PTM Hydroxylated by HIF1AN.PTM Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1.PTM Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.SIMILARITY Belongs to the NOTCH family. UniProt Q04721 1697 EQUAL 2471 EQUAL Reactome Database ID Release 81 157942 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=157942 Reactome R-HSA-157942 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-157942.1 1 Reactome Database ID Release 81 2127289 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=2127289 Reactome R-HSA-2127289 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-2127289.1 Reactome Database ID Release 81 9604665 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=9604665 Reactome R-HSA-9604665 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-9604665.1 LEFT-TO-RIGHT NOTCH4 binds SMAD3 NOTCH4 intracellular domain fragment (NICD4) binds phosphorylated SMAD3 upon activation of TGF-beta signaling. (Sun et al. 2005, Grabias and Konstantopoulos 2013). NICD4 may also bind SMAD2 and SMAD4 (Sun et al. 2005). NICD4 promotes ubiquitination and proteasome-mediated degradation of SMAD3 through and unknown mechanism (Grabias and Konstantopoulos 2013) and inhibits transcription mediated by the heterotrimer of SMAD3, SMAD2 and SMAD4, thus negatively regulating TGF-beta signaling (Sun et al. 2005, Grabias and Konstantopoulos 2013). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 p-2S-SMAD3 p-S423,S425-SMAD3 Phospho-SMAD 3 Mothers against decapentaplegic homolog 3 Reactome DB_ID: 171184 UniProt:P84022 SMAD3 SMAD3 MADH3 FUNCTION Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; in the absence of TGF-beta (PubMed:9670020). Homooligomer; in the presence of TGF-beta (PubMed:9670020). Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex (PubMed:9670020, PubMed:11224571, PubMed:15799969, PubMed:15350224). Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (PubMed:9892009). Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4 (PubMed:16449645). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling (PubMed:16751101). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (PubMed:9311995). Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus (PubMed:15601644, PubMed:15647271). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3 (PubMed:9843571, PubMed:15588252). This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity (PubMed:9843571, PubMed:15588252). Interacts with TGFBR1 (PubMed:9311995). Interacts with TGFB1I1 (PubMed:15561701). Interacts with PRDM16 (PubMed:19049980). Interacts with SNW1 (PubMed:11278756). Interacts (via MH2 domain) with ZFYVE9 (PubMed:9865696, PubMed:12154125). Interacts with HDAC1 (PubMed:19049980). Interacts with TGIF2 (PubMed:11427533). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with DACH1; the interaction inhibits the TGF-beta signaling (PubMed:14525983). Interacts with RBPMS (PubMed:17099224). Interacts (via MH2 domain) with MECOM (PubMed:9665135, PubMed:15897867). Interacts with WWTR1 (via its coiled-coil domain) (PubMed:18568018). Interacts with SKI; the interaction represses SMAD3 transcriptional activity (PubMed:19049980). Interacts with MEN1 (PubMed:11274402). Interacts with IL1F7 (PubMed:20935647). Interaction with CSNK1G2 (PubMed:18794808). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487). Interacts with PMEPA1 (PubMed:20129061). Interacts with ZNF451 (PubMed:24324267). Interacts with ZFHX3 (PubMed:25105025). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (PubMed:24613385). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). Interacts with AIP1 (By similarity). Interacts (via MH2 domain) with CITED2 (via C-terminus) (By similarity). Interacts with HGS (By similarity). Interacts with WWP1 (By similarity). Interacts with TTRAP (By similarity). Interacts with FOXL2 (By similarity). Interacts with PML (By similarity). Interacts with NEDD4L; the interaction requires TGF-beta stimulation (By similarity). Interacts with ZC3H3 (By similarity). Interacts with TGIF. Interacts with CREBBP. Interacts with ATF2.SUBUNIT (Microbial infection) Interacts with SARS-CoV nucleoprotein.DOMAIN The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.DOMAIN The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.PTM Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.PTM Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.PTM Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.PTM Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).SIMILARITY Belongs to the dwarfin/SMAD family. UniProt P84022 423 EQUAL 425 EQUAL 1 EQUAL 425 EQUAL Reactome Database ID Release 81 171184 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=171184 Reactome R-HSA-171184 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-171184.1 NICD4:p-S423,S425-SMAD3 Reactome DB_ID: 9605420 1 1 Reactome Database ID Release 81 9605420 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=9605420 Reactome R-HSA-9605420 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-9605420.1 Reactome Database ID Release 81 9605414 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=9605414 Reactome R-HSA-9605414 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-9605414.1 16007227 Pubmed 2005 Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling Sun, Youping Lowther, William Kato, Katsuaki Bianco, Caterina Kenney, Nicholas Strizzi, L Raafat, Dina Hirota, Morihisa Khan, Nadia I Bargo, Sharon Jones, Brenda Salomon, David Callahan, Robert Oncogene 24:5365-74 23576639 Pubmed 2013 Notch4-dependent antagonism of canonical TGF-β1 signaling defines unique temporal fluctuations of SMAD3 activity in sheared proximal tubular epithelial cells Grabias, Bryan M Konstantopoulos, Konstantinos Am. J. Physiol. Renal Physiol. 305:F123-33 GENE ONTOLOGY GO:0030512 Reactome Database ID Release 81 9013695 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=9013695 Reactome R-HSA-9013695 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-9013695.1 GENE ONTOLOGY GO:0006355 Negative regulation of NOTCH4 signaling NOTCH4 signaling can be negatively regulated at the level of nuclear translocation of the NOTCH4 intracellular domain fragment (NICD4). AKT-mediated phosphorylation of NICD4 promotes binding of NICD4 with 14-3-3-zeta (YWHAZ), leading to retention of NICD4 in the cytosol (Ramakrishnan et al. 2015).<br><br>The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4, targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004).<br><br>Binding of NOTCH4 to ELOC (elongin C) is involved in proteasome-mediated degradation of NOTCH4, but the exact mechanism has not been elucidated (Cummins et al. 2011). MDM2, a TP53-induced ubiquitin ligase, was reported to ubiquitinate NICD4 and target it for degradation in response to TP53 activation (Sun et al. 2011).<br><br>NOTCH4 signaling is inhibited by binding of NICD4 to the transforming acidic coiled-coil protein-3, but he mechanism is not known (Bargo et al. 2010). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 LEFT-TO-RIGHT 2.7.11.1 AKT1 phosphorylates NOTCH4 Recombinant human AKT1 phosphorylates recombinant human NICD4 on four AKT-target sites conserved in primates: S1495, S1847, S1865 and S1917 (Ramakrishnan et al. 2015). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 113592 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=113592 Reactome R-ALL-113592 5 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-ALL-113592.5 COMPOUND C00002 4 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 29370 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=29370 Reactome R-ALL-29370 5 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-ALL-29370.5 COMPOUND C00008 4 ACTIVATION PKB p-T308,S473-AKT1 p-S473,T308-AKT1 p-T308, S473-AKT1 RAC-alpha serine/threonine kinase RAC-PK-alpha Protein kinase B C-AKT Reactome DB_ID: 198356 UniProt:P31749 AKT1 AKT1 PKB RAC FUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline.SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).TISSUE SPECIFICITY Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.PTM Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.MISCELLANEOUS (2S)-2-(4-chlorobenzyl)-3-oxo-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]propan-1-amine corresponds to compound 44.MISCELLANEOUS 5-(5-chloro-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine corresponds to compound 8b.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain. UniProt P31749 308 EQUAL O-phospho-L-threonine MOD MOD:00047 473 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 81 198356 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=198356 Reactome R-HSA-198356 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-198356.1 GENE ONTOLOGY GO:0004674 Reactome Database ID Release 81 450501 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=450501 Reactome Database ID Release 81 9604328 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=9604328 Reactome R-HSA-9604328 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-9604328.2 GENE ONTOLOGY GO:0045746 LEFT-TO-RIGHT p-4S-NICD4 binds YWHAZ AKT1-mediated phosphorylation of NOTCH4 intracellular domain fragment NICD4 leads to binding of NICD4 to 14-3-3-zeta (YWHAZ). Binding to YWHAZ sequesters NICD4 to the cytosol, preventing its trafficking to the nucleus, and thus negatively regulates NOTCH4 signaling (Ramakrishnan et al. 2015). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 Reactome Database ID Release 81 9604387 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=9604387 Reactome R-HSA-9604387 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-9604387.1 LEFT-TO-RIGHT Unknown kinase phosphorylates NICD4 Unknown protein kinase phosphorylates the C-terminus of NICD4 (NOTCH4 intracellular domain fragment) (Wu et al. 2001). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 p-NICD4 p-NOTCH4(1467-2003) p-NICD 4 fragment p-N4ICD Reactome DB_ID: 9604611 phosphorylated residue MOD MOD:00696 1467 EQUAL 2003 EQUAL Reactome Database ID Release 81 9604611 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=9604611 Reactome R-HSA-9604611 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-9604611.1 ACTIVATION Unknown protein kinase Reactome DB_ID: 9604605 Reactome Database ID Release 81 9604605 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=9604605 Reactome R-HSA-9604605 3 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-9604605.3 ChEBI 36080 GENE ONTOLOGY GO:0004672 Reactome Database ID Release 81 9604609 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=9604609 Reactome Database ID Release 81 9604606 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=9604606 Reactome R-HSA-9604606 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-9604606.1 11585921 Pubmed 2001 SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation Wu, G Lyapina, S Das, I Li, J Gurney, M Pauley, A Chui, I Deshaies, RJ Kitajewski, J Mol Cell Biol 21:7403-15 LEFT-TO-RIGHT FBXW7 promotes ubiquitination of p-NICD4 The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4 (NOTCH4 intracellular domain fragment), targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004). Notch4 level also increases when Fbxw7 is downregulated by RNA in mouse embryonic fibroblasts (Mao et al. 2004). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 Converted from EntitySet in Reactome Ub Ubiquitin UBIQ_HUMAN Reactome DB_ID: 68524 RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939849 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939849 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=939849 Reactome R-HSA-939849 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-939849.1 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939844 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939844 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=939844 Reactome R-HSA-939844 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-939844.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939847 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939847 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=939847 Reactome R-HSA-939847 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-939847.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939870 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939870 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=939870 Reactome R-HSA-939870 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-939870.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939854 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939854 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=939854 Reactome R-HSA-939854 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-939854.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939871 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939871 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=939871 Reactome R-HSA-939871 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-939871.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939869 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939869 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=939869 Reactome R-HSA-939869 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-939869.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939853 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939853 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=939853 Reactome R-HSA-939853 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-939853.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939857 229 EQUAL 304 EQUAL Reactome Database ID Release 81 939857 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=939857 Reactome R-HSA-939857 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-939857.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939863 305 EQUAL 380 EQUAL Reactome Database ID Release 81 939863 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=939863 Reactome R-HSA-939863 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-939863.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939856 381 EQUAL 456 EQUAL Reactome Database ID Release 81 939856 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=939856 Reactome R-HSA-939856 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-939856.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939862 457 EQUAL 532 EQUAL Reactome Database ID Release 81 939862 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=939862 Reactome R-HSA-939862 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-939862.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939866 533 EQUAL 608 EQUAL Reactome Database ID Release 81 939866 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=939866 Reactome R-HSA-939866 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-939866.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939868 609 EQUAL 684 EQUAL Reactome Database ID Release 81 939868 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=939868 Reactome R-HSA-939868 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-939868.1 Reactome Database ID Release 81 68524 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=68524 Reactome R-HSA-68524 3 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-68524.3 3 PolyUb-p-NICD4 PolyUb-p-NOTCH4(1467-2003) PolyUb-p-NICD 4 fragment PolyUb-p-N4ICD Reactome DB_ID: 9604624 ubiquitinylated lysine MOD MOD:01148 1467 EQUAL 2003 EQUAL Reactome Database ID Release 81 9604624 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=9604624 Reactome R-HSA-9604624 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-9604624.1 ACTIVATION FBXW7:SKP1:CUL1:RBX1 Reactome DB_ID: 1604469 CUL1 Cul-1_1 Reactome DB_ID: 187551 UniProt:Q13616 CUL1 CUL1 FUNCTION Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and exchange of the substrate recognition component is mediated by TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68 (PubMed:25704143, PubMed:25503564). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of CCNE1, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO1) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit (PubMed:10230406, PubMed:15145941, PubMed:15531760, PubMed:16714087, PubMed:16797541, PubMed:17098746, PubMed:18203720, PubMed:20596027, PubMed:22405651, PubMed:22113614, PubMed:23263282, PubMed:23431138, PubMed:25503564, PubMed:11961546, PubMed:22748924). Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXW2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF (PubMed:20596027). Interacts with CCNF (PubMed:26818844). Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:22405651). Interacts with CHEK2; mediates CHEK2 ubiquitination and regulates its function. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction mediates the exchange of the F-box substrate-specific subunit. Can self-associate. Interacts with FBXW8. Interacts with RNF7. Interacts with CUL7; the interaction seems to be mediated by FBXW8. Interacts with TRIM21. Interacts with COPS2. Interacts with UBE2M (PubMed:21940857). Identified in a complex with RBX1 and GLMN (PubMed:22405651, PubMed:22748924). Interacts with CEP68 as part of the SCF(FBXW11) complex; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT (PubMed:25503564). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). Interacts with COPS9 isoform 2 (PubMed:23776465). Interacts with UBXN1 (PubMed:28152074). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (By similarity). Interacts with NOTCH2 (PubMed:29149593). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this complex is bridged by CUL1 (PubMed:24192928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:24192928, PubMed:26906416, PubMed:23201271, PubMed:21940857, PubMed:25349211, PubMed:28581483).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus BPLF1.SUBUNIT (Microbial infection) Interacts with Human adenovirus early E1A protein; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBXW7) complex.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.TISSUE SPECIFICITY Expressed in lung fibroblasts.PTM Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (PubMed:10597293, PubMed:10713156, PubMed:15537541, PubMed:18805092).PTM (Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome (PubMed:20190741).SIMILARITY Belongs to the cullin family. UniProt Q13616 1 EQUAL 776 EQUAL Reactome Database ID Release 81 187551 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=187551 Reactome R-HSA-187551 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-187551.1 1 ZYP RBX1 RNF75 ROC1 E3 ubiquitin-protein ligase RBX1 Reactome DB_ID: 1234142 UniProt:P62877 RBX1 RBX1 RNF75 ROC1 FUNCTION E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair (PubMed:10230407, PubMed:10579999, PubMed:15983046, PubMed:16678110, PubMed:19112177, PubMed:19679664, PubMed:23455478, PubMed:27565346, PubMed:29769719, PubMed:11961546, PubMed:22748924). CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets (PubMed:27565346). The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2 (PubMed:11961546). Part of a SCF-like complex consisting of CUL7, RBX1, SKP1 and FBXW8. Part of CBC(VHL) complexes with elongin BC complex (ELOB and ELOC), CUL2 or CUL5 and VHL. Part of the CSA complex (DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Part of multisubunit E3 ubiquitin ligase complexes with elongin BC complex (ELOB and ELOC), CUL2 and MED8; elongin BC complex (ELOB and ELOC), CUL5 and MUF1. Part of multisubunit complexes with elongin BC complex (ELOB and ELOC), elongin A/ELOA or SOCS1 or WSB1 and CUL5. Interacts directly with CUL1 and probably also with CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7. Interacts with CDC34 (PubMed:22748924). Interacts with GLMN. GLMN competes for the binding site of the E2 ubiquitin-conjugating enzyme CDC34 and disrupts CDC34 binding (PubMed:22748924). Interacts with COPS6. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Part of an E3 ligase complex composed of RBX1, DDB1, DDB2 and CUL4A or CUL4B. Interacts with UBE2M. Part of a SCF complex consisting of CUL1, FBXO3, RBX1 and SKP1; this complex interacts with PML via FBXO3. Component of the SCF(Cyclin F) complex consisting of CUL1, RBX1, SKP1 and CCNF. Identified in a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex together with HINT1 and CDC34. Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein. Part of the BCR(ENC1) complex containing ENC1. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KLHL41) complex containing KLHL41. Part of the BCR(KEAP1) complex containing KEAP1. Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with NOTCH2 (PubMed:29149593). Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (PubMed:23455478). Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:26906416, PubMed:24192928, PubMed:25349211). Component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7 (PubMed:25684205).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 protein E1A; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBW7) complex.TISSUE SPECIFICITY Widely expressed.DOMAIN The RING-type zinc finger domain is essential for ubiquitin ligase activity (PubMed:10230407). It coordinates an additional third zinc ion (PubMed:11961546, PubMed:22748924).SIMILARITY Belongs to the RING-box family. UniProt P62877 2 EQUAL 108 EQUAL Reactome Database ID Release 81 1234142 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=1234142 Reactome R-HSA-1234142 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-1234142.1 1 Converted from EntitySet in Reactome FBXW7alpha/gamma Reactome DB_ID: 1602299 FBXW7 FBXW7alpha FBXW7-1 Reactome DB_ID: 1602296 UniProt:Q969H0-1 FBXW7 FBXW7 FBW7 FBX30 SEL10 FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).SUBUNIT Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation (PubMed:22608923, PubMed:17434132, PubMed:28007894). Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 (PubMed:11565034, PubMed:15103331, PubMed:22748924, PubMed:26774286, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with SKP1 (PubMed:11585921, PubMed:17434132, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1 (PubMed:28007894). Interacts with cyclin-E (CCNE1 or CCNE2) (PubMed:11565034, PubMed:17434132). Interacts with PSEN1 (PubMed:12354302). Forms a trimeric complex with NOTCH1 and SGK1 (PubMed:21147854). Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD (PubMed:11585921). Interacts with NOTCH2 intracellular domain (N2ICD) (PubMed:29149593). Interacts with MYC (when phosphorylated) (PubMed:17873522, PubMed:25775507, PubMed:28007894). Interacts with USP28, leading to counteract ubiquitination of MYC (PubMed:17873522). Interacts with JUN (PubMed:14739463, PubMed:22608923). Found in a complex with JUN and PRR7 (PubMed:27458189). Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts (when phosphorylated at Thr-205) with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Interacts with UBE2QL1 (PubMed:24000165). Interacts with FAM83D; promotes FBXW7 degradation (PubMed:24344117). Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with STOML1 (PubMed:23082202). Interacts with NFE2L1 (By similarity). Interacts with USP36, leading to counteract ubiquitination of MYC (PubMed:25775507). Interacts with NR1D1 (PubMed:27238018).SUBUNIT (Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).DOMAIN The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.DOMAIN The F-box domain mediates interaction with SKP1.PTM Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).PTM Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923). UniProt Isoform Q969H0-1 1 EQUAL 707 EQUAL Reactome Database ID Release 81 1602296 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=1602296 Reactome R-HSA-1602296 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-1602296.2 FBXW7-4 FBXW7gamma Reactome DB_ID: 1602297 UniProt:Q969H0-4 FBXW7 FBXW7 FBW7 FBX30 SEL10 FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).SUBUNIT Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation (PubMed:22608923, PubMed:17434132, PubMed:28007894). Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 (PubMed:11565034, PubMed:15103331, PubMed:22748924, PubMed:26774286, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with SKP1 (PubMed:11585921, PubMed:17434132, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1 (PubMed:28007894). Interacts with cyclin-E (CCNE1 or CCNE2) (PubMed:11565034, PubMed:17434132). Interacts with PSEN1 (PubMed:12354302). Forms a trimeric complex with NOTCH1 and SGK1 (PubMed:21147854). Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD (PubMed:11585921). Interacts with NOTCH2 intracellular domain (N2ICD) (PubMed:29149593). Interacts with MYC (when phosphorylated) (PubMed:17873522, PubMed:25775507, PubMed:28007894). Interacts with USP28, leading to counteract ubiquitination of MYC (PubMed:17873522). Interacts with JUN (PubMed:14739463, PubMed:22608923). Found in a complex with JUN and PRR7 (PubMed:27458189). Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts (when phosphorylated at Thr-205) with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Interacts with UBE2QL1 (PubMed:24000165). Interacts with FAM83D; promotes FBXW7 degradation (PubMed:24344117). Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with STOML1 (PubMed:23082202). Interacts with NFE2L1 (By similarity). Interacts with USP36, leading to counteract ubiquitination of MYC (PubMed:25775507). Interacts with NR1D1 (PubMed:27238018).SUBUNIT (Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).DOMAIN The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.DOMAIN The F-box domain mediates interaction with SKP1.PTM Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).PTM Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923). UniProt Isoform Q969H0-4 1 EQUAL 589 EQUAL Reactome Database ID Release 81 1602297 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=1602297 Reactome R-HSA-1602297 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-1602297.1 Reactome Database ID Release 81 1602299 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=1602299 Reactome R-HSA-1602299 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-1602299.1 1 SKP1 Skp1 Reactome DB_ID: 187538 UniProt:P63208 SKP1 SKP1 EMC19 OCP2 SKP1A TCEB1L FUNCTION Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2 (PubMed:25704143). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with KDM2B, forming heterodimers (PubMed:27568929). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit. Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXw2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:28727686). Interacts with CEP68 (PubMed:25503564). Interacts with NOTCH2 (PubMed:29149593). Interacts with FBXW15 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (PubMed:30033217).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.SIMILARITY Belongs to the SKP1 family. UniProt P63208 2 EQUAL 163 EQUAL Reactome Database ID Release 81 187538 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=187538 Reactome R-HSA-187538 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-187538.1 1 Reactome Database ID Release 81 1604469 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=1604469 Reactome R-HSA-1604469 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-1604469.1 GENE ONTOLOGY GO:0061630 Reactome Database ID Release 81 9604630 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=9604630 Reactome Database ID Release 81 9604629 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=9604629 Reactome R-HSA-9604629 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-9604629.1 15592418 Pubmed 2004 Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene Mao, Jian-Hua Perez-Losada, Jesus Wu, Di Delrosario, Reyno Tsunematsu, Ryosuke Nakayama, Keiichi I Brown, Ken Bryson, Sheila Balmain, Allan Nature 432:775-9 LEFT-TO-RIGHT Proteasome degrades ubiquitinated NICD4 FBXW7-mediated ubiquitination targets NICD4 (NOTCH4 intracellular domain fragment) for proteasome-mediated degradation (Wu et al. 2001). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 3 ACTIVATION 26S proteasome Reactome DB_ID: 177750 p31 PSMD8 26S proteasome non-ATPase regulatory subunit 8 26S proteasome regulatory subunit S14 Reactome DB_ID: 174318 UniProt:P48556 PSMD8 PSMD8 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator. UniProt P48556 1 EQUAL 350 EQUAL Reactome Database ID Release 81 174318 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=174318 Reactome R-HSA-174318 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-174318.1 1 PSME3 Proteasome activator complex subunit 3 Proteasome activator 28-gamma subunit PA28gamma PA28g Activator of multicatalytic protease subunit 3 11S regulator complex gamma subunit REG-gamma Ki nuclear autoantigen Reactome DB_ID: 174310 UniProt:P61289 PSME3 PSME3 FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family. UniProt P61289 2 EQUAL 254 EQUAL Reactome Database ID Release 81 174310 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=174310 Reactome R-HSA-174310 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-174310.1 1 PSMB7 Proteasome subunit beta type 7 Proteasome subunit beta type 7 precursor Proteasome subunit Z Macropain chain Z Multicatalytic endopeptidase complex chain Z Reactome DB_ID: 174331 UniProt:Q99436 PSMB7 PSMB7 Z FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family. UniProt Q99436 44 EQUAL 277 EQUAL Reactome Database ID Release 81 174331 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=174331 Reactome R-HSA-174331 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-174331.1 1 PSMD12 26S proteasome non-ATPase regulatory subunit 12 26S proteasome regulatory subunit p55 Reactome DB_ID: 174339 UniProt:O00232 PSMD12 PSMD12 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family. UniProt O00232 2 EQUAL 456 EQUAL Reactome Database ID Release 81 174339 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=174339 Reactome R-HSA-174339 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-174339.1 1 PSMD10 26S proteasome non-ATPase regulatory subunit 10 26S proteasome regulatory subunit p28 Gankyrin Reactome DB_ID: 174322 UniProt:O75832 PSMD10 PSMD10 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt O75832 1 EQUAL 226 EQUAL Reactome Database ID Release 81 174322 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=174322 Reactome R-HSA-174322 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-174322.1 1 p42A PSMD6 26S proteasome non-ATPase regulatory subunit 6 26S proteasome regulatory subunit S10 Proteasome regulatory particle subunit p44S10 Reactome DB_ID: 174316 UniProt:Q15008 PSMD6 PSMD6 KIAA0107 PFAAP4 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family. UniProt Q15008 1 EQUAL 389 EQUAL Reactome Database ID Release 81 174316 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=174316 Reactome R-HSA-174316 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-174316.1 1 PSMD9 26S proteasome non-ATPase regulatory subunit 9 26S proteasome regulatory subunit p27 Reactome DB_ID: 174321 UniProt:O00233 PSMD9 PSMD9 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome. UniProt O00233 1 EQUAL 223 EQUAL Reactome Database ID Release 81 174321 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=174321 Reactome R-HSA-174321 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-174321.1 1 PSME2 Proteasome activator complex subunit 2 Proteasome activator 28-beta subunit PA28beta PA28b Activator of multicatalytic protease subunit 2 11S regulator complex beta subunit REG-beta Reactome DB_ID: 174350 UniProt:Q9UL46 PSME2 PSME2 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q9UL46 2 EQUAL 239 EQUAL Reactome Database ID Release 81 174350 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=174350 Reactome R-HSA-174350 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-174350.1 1 PSMB2 Proteasome subunit beta type 2 Proteasome component C7-I Macropain subunit C7-I Multicatalytic endopeptidase complex subunit C7-I Reactome DB_ID: 174335 UniProt:P49721 PSMB2 PSMB2 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P49721 1 EQUAL 201 EQUAL Reactome Database ID Release 81 174335 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=174335 Reactome R-HSA-174335 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-174335.1 1 PSMB10 Proteasome subunit beta type 10 Proteasome subunit beta type 10 precursor Proteasome MECl-1 Macropain subunit MECl-1 Multicatalytic endopeptidase complex subunit MECl-1 Reactome DB_ID: 174349 UniProt:P40306 PSMB10 PSMB10 LMP10 MECL1 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P40306 40 EQUAL 273 EQUAL Reactome Database ID Release 81 174349 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=174349 Reactome R-HSA-174349 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-174349.1 1 PSMD11 26S proteasome non-ATPase regulatory subunit 11 26S proteasome regulatory subunit S9 26S proteasome regulatory subunit p44.5 Reactome DB_ID: 174327 UniProt:O00231 PSMD11 PSMD11 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family. UniProt O00231 2 EQUAL 422 EQUAL Reactome Database ID Release 81 174327 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=174327 Reactome R-HSA-174327 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-174327.1 1 PSMD5 26S proteasome non-ATPase regulatory subunit 5 26S proteasome subunit S5B 26S protease subunit S5 basic Reactome DB_ID: 174346 UniProt:Q16401 PSMD5 PSMD5 KIAA0072 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt Q16401 2 EQUAL 504 EQUAL Reactome Database ID Release 81 174346 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=174346 Reactome R-HSA-174346 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-174346.1 1 PSMD7 26S proteasome non-ATPase regulatory subunit 7 26S proteasome regulatory subunit S12 Proteasome subunit p40 Mov34 protein homolog Reactome DB_ID: 174309 UniProt:P51665 PSMD7 PSMD7 MOV34L FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family. UniProt P51665 1 EQUAL 324 EQUAL Reactome Database ID Release 81 174309 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=174309 Reactome R-HSA-174309 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-174309.1 1 PSMD13 26S proteasome non-ATPase regulatory subunit 13 26S proteasome regulatory subunit S11 26S proteasome regulatory subunit p40.5 Reactome DB_ID: 174326 UniProt:Q9UNM6 PSMD13 PSMD13 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family. UniProt Q9UNM6 1 EQUAL 376 EQUAL Reactome Database ID Release 81 174326 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=174326 Reactome R-HSA-174326 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-174326.1 1 PSMB9 Proteasome subunit beta type 9 Proteasome subunit beta type 9 precursor Proteasome chain 7 Macropain chain 7 Multicatalytic endopeptidase complex chain 7 RING12 protein Low molecular mass protein 2 Reactome DB_ID: 174334 UniProt:P28065 PSMB9 PSMB9 LMP2 PSMB6i RING12 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family. UniProt P28065 21 EQUAL 219 EQUAL Reactome Database ID Release 81 174334 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=174334 Reactome R-HSA-174334 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-174334.1 1 p44 PSMC6 26S protease regulatory subunit S10B Proteasome subunit p42 Conserved ATPase domain protein 44 CADp44 Reactome DB_ID: 174319 UniProt:P62333 PSMC6 PSMC6 SUG2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924. UniProt P62333 1 EQUAL 389 EQUAL Reactome Database ID Release 81 174319 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=174319 Reactome R-HSA-174319 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-174319.1 1 PSMB6 Proteasome subunit beta type 6 Proteasome subunit beta type 6 precursor Proteasome delta chain Macropain delta chain Multicatalytic endopeptidase complex delta chain Proteasome subunit Y Reactome DB_ID: 174342 UniProt:P28072 PSMB6 PSMB6 LMPY Y FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P28072 35 EQUAL 239 EQUAL Reactome Database ID Release 81 174342 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=174342 Reactome R-HSA-174342 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-174342.1 1 PSMD2 26S proteasome non-ATPase regulatory subunit 2 26S proteasome regulatory subunit S2 26S proteasome subunit p97 Tumor necrosis factor type 1 receptor associated protein 2 55.11 protein Reactome DB_ID: 174311 UniProt:Q13200 PSMD2 PSMD2 TRAP2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family. UniProt Q13200 1 EQUAL 908 EQUAL Reactome Database ID Release 81 174311 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=174311 Reactome R-HSA-174311 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-174311.1 1 PSMD1 26S proteasome non-ATPase regulatory subunit 1 26S proteasome regulatory subunit S1 26S proteasome subunit p112 Reactome DB_ID: 174348 UniProt:Q99460 PSMD1 PSMD1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family. UniProt Q99460 1 EQUAL 953 EQUAL Reactome Database ID Release 81 174348 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=174348 Reactome R-HSA-174348 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-174348.1 1 AF PSMD4 26S proteasome non-ATPase regulatory subunit 4 26S proteasome regulatory subunit S5A Rpn10 Multiubiquitin chain binding protein Antisecretory factor-1 ASF Reactome DB_ID: 174330 UniProt:P55036 PSMD4 PSMD4 MCB1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family. UniProt P55036 1 EQUAL 377 EQUAL Reactome Database ID Release 81 174330 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=174330 Reactome R-HSA-174330 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-174330.1 1 p27K PSMA6 Proteasome subunit alpha type 6 Proteasome iota chain Macropain iota chain Multicatalytic endopeptidase complex iota chain 27 kDa prosomal protein PROS-27 Reactome DB_ID: 174314 UniProt:P60900 PSMA6 PSMA6 PROS27 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family. UniProt P60900 1 EQUAL 246 EQUAL Reactome Database ID Release 81 174314 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=174314 Reactome R-HSA-174314 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-174314.1 1 PSMA5 Proteasome subunit alpha type 5 Proteasome zeta chain Macropain zeta chain Multicatalytic endopeptidase complex zeta chain Reactome DB_ID: 174340 UniProt:P28066 PSMA5 PSMA5 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family. UniProt P28066 1 EQUAL 241 EQUAL Reactome Database ID Release 81 174340 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=174340 Reactome R-HSA-174340 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-174340.1 1 HSN3 PSMB4 Proteasome subunit beta type 4 Proteasome subunit beta type 4 precursor Proteasome beta chain Macropain beta chain Multicatalytic endopeptidase complex beta chain Proteasome chain 3 HsBPROS26 Reactome DB_ID: 174343 UniProt:P28070 PSMB4 PSMB4 PROS26 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result. UniProt P28070 46 EQUAL 264 EQUAL Reactome Database ID Release 81 174343 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=174343 Reactome R-HSA-174343 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-174343.1 1 PSMA1 Proteasome subunit alpha type 1 Proteasome component C2 Macropain subunit C2 Multicatalytic endopeptidase complex subunit C2 Proteasome nu chain 30 kDa prosomal protein PROS-30 Reactome DB_ID: 174333 UniProt:P25786 PSMA1 PSMA1 HC2 NU PROS30 PSC2 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family. UniProt P25786 1 EQUAL 263 EQUAL Reactome Database ID Release 81 174333 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=174333 Reactome R-HSA-174333 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-174333.1 1 PSME1 Proteasome activator complex subunit 1 Proteasome activator 28-alpha subunit PA28alpha PA28a Activator of multicatalytic protease subunit 1 11S regulator complex alpha subunit REG-alpha Interferon gamma up-regulated I-5111 protein IGUP I-5111 Reactome DB_ID: 174320 UniProt:Q06323 PSME1 PSME1 IFI5111 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q06323 1 EQUAL 249 EQUAL Reactome Database ID Release 81 174320 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=174320 Reactome R-HSA-174320 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-174320.1 1 PSMC2 26S protease regulatory subunit 7 MSS1 protein Reactome DB_ID: 174332 UniProt:P35998 PSMC2 PSMC2 MSS1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775, PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase (PubMed:9295362, PubMed:10409732). Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.PTM Monoubiquitinated by RNF181.SIMILARITY Belongs to the AAA ATPase family. UniProt P35998 2 EQUAL 433 EQUAL Reactome Database ID Release 81 174332 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=174332 Reactome R-HSA-174332 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-174332.1 1 PSMA2 Proteasome subunit alpha type 2 Proteasome component C3 Macropain subunit C3 Multicatalytic endopeptidase complex subunit C3 Reactome DB_ID: 174345 UniProt:P25787 PSMA2 PSMA2 HC3 PSC3 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P25787 2 EQUAL 234 EQUAL Reactome Database ID Release 81 174345 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=174345 Reactome R-HSA-174345 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-174345.1 1 PSMA4 Proteasome subunit alpha type 4 Proteasome component C9 Macropain subunit C9 Multicatalytic endopeptidase complex subunit C9 Proteasome subunit L Reactome DB_ID: 174324 UniProt:P25789 PSMA4 PSMA4 HC9 PSC9 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family. UniProt P25789 1 EQUAL 261 EQUAL Reactome Database ID Release 81 174324 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=174324 Reactome R-HSA-174324 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-174324.1 1 SEM1 SHFM1 DSS1 26S proteasome complex subunit DSS1 DSS1_HUMAN Reactome DB_ID: 8866665 UniProt:P60896 SEM1 SEM1 DSS1 SHFDG1 SHFM1 C7orf76 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family. UniProt P60896 1 EQUAL 70 EQUAL Reactome Database ID Release 81 8866665 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=8866665 Reactome R-HSA-8866665 3 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-8866665.3 1 PSMB3 Proteasome subunit beta type 3 Proteasome theta chain Proteasome chain 13 Proteasome component C10-II Reactome DB_ID: 174341 UniProt:P49720 PSMB3 PSMB3 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family. UniProt P49720 2 EQUAL 205 EQUAL Reactome Database ID Release 81 174341 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=174341 Reactome R-HSA-174341 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-174341.1 1 PSMB8 Proteasome subunit beta type 8 Proteasome subunit beta type 8 precursor Proteasome component C13 Macropain subunit C13 Multicatalytic endopeptidase complex subunit C13 Reactome DB_ID: 174336 UniProt:P28062 PSMB8 PSMB8 LMP7 PSMB5i RING10 Y2 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P28062 73 EQUAL 276 EQUAL Reactome Database ID Release 81 174336 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=174336 Reactome R-HSA-174336 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-174336.1 1 PSMC3 26S protease regulatory subunit 6A TAT-binding protein 1 TBP-1 Proteasome subunit P50 Reactome DB_ID: 174313 UniProt:P17980 PSMC3 PSMC3 TBP1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family. UniProt P17980 1 EQUAL 439 EQUAL Reactome Database ID Release 81 174313 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=174313 Reactome R-HSA-174313 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-174313.1 1 PSMF1 Proteasome inhibitor PI31 subunit hPI31 Reactome DB_ID: 174308 UniProt:Q92530 PSMF1 PSMF1 FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family. UniProt Q92530 1 EQUAL 271 EQUAL Reactome Database ID Release 81 174308 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=174308 Reactome R-HSA-174308 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-174308.1 1 PSMD3 26S proteasome non-ATPase regulatory subunit 3 26S proteasome regulatory subunit S3 Proteasome subunit p58 Reactome DB_ID: 174328 UniProt:O43242 PSMD3 PSMD3 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family. UniProt O43242 1 EQUAL 534 EQUAL Reactome Database ID Release 81 174328 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=174328 Reactome R-HSA-174328 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-174328.1 1 PSMA3 Proteasome subunit alpha type 3 Proteasome component C8 Macropain subunit C8 Multicatalytic endopeptidase complex subunit C8 Reactome DB_ID: 174323 UniProt:P25788 PSMA3 PSMA3 HC8 PSC8 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family. UniProt P25788 2 EQUAL 255 EQUAL Reactome Database ID Release 81 174323 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=174323 Reactome R-HSA-174323 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-174323.1 1 PSMA7 Proteasome subunit alpha type 7 Proteasome subunit RC6-1 Proteasome subunit XAPC7 Reactome DB_ID: 174351 UniProt:O14818 PSMA7 PSMA7 HSPC FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family. UniProt O14818 1 EQUAL 248 EQUAL Reactome Database ID Release 81 174351 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=174351 Reactome R-HSA-174351 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-174351.1 1 PSMB5 Proteasome subunit beta type 5 Proteasome subunit beta type 5 precursor Proteasome epsilon chain Macropain epsilon chain Multicatalytic endopeptidase complex epsilon chain Proteasome subunit X Proteasome chain 6 Proteasome subunit MB1 Reactome DB_ID: 174344 UniProt:P28074 PSMB5 PSMB5 LMPX MB1 X FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family. UniProt P28074 60 EQUAL 263 EQUAL Reactome Database ID Release 81 174344 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=174344 Reactome R-HSA-174344 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-174344.1 1 PSMC5 Probable 26S protease regulatory subunit 8 Reactome DB_ID: 174312 UniProt:P62195 PSMC5 PSMC5 SUG1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family. UniProt P62195 2 EQUAL 406 EQUAL Reactome Database ID Release 81 174312 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=174312 Reactome R-HSA-174312 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-174312.1 1 PSMD14 26S proteasome-associated pad1 homolog Reactome DB_ID: 174329 UniProt:O00487 PSMD14 PSMD14 POH1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily. UniProt O00487 1 EQUAL 310 EQUAL Reactome Database ID Release 81 174329 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=174329 Reactome R-HSA-174329 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-174329.1 1 PSMB1 Proteasome subunit beta type 1 Proteasome component C5 Macropain subunit C5 Multicatalytic endopeptidase complex subunit C5 Proteasome gamma chain Reactome DB_ID: 174347 UniProt:P20618 PSMB1 PSMB1 PSC5 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family. UniProt P20618 29 EQUAL 241 EQUAL Reactome Database ID Release 81 174347 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=174347 Reactome R-HSA-174347 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-174347.1 1 PSMC1 26S protease regulatory subunit 4 P26s4 Reactome DB_ID: 174338 UniProt:P62191 PSMC1 PSMC1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family. UniProt P62191 2 EQUAL 440 EQUAL Reactome Database ID Release 81 174338 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=174338 Reactome R-HSA-174338 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-174338.1 1 PSMC4 26S protease regulatory subunit 6B MIP224 MB67 interacting protein TAT-binding protein-7 TBP-7 Reactome DB_ID: 174315 UniProt:P43686 PSMC4 PSMC4 MIP224 TBP7 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family. UniProt P43686 1 EQUAL 418 EQUAL Reactome Database ID Release 81 174315 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=174315 Reactome R-HSA-174315 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-174315.1 1 Reactome Database ID Release 81 177750 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=177750 Reactome R-HSA-177750 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-177750.2 ComplexPortal CPX-5993 GENE ONTOLOGY GO:0004175 Reactome Database ID Release 81 174087 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=174087 Reactome Database ID Release 81 9604642 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=9604642 Reactome R-HSA-9604642 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-9604642.1 LEFT-TO-RIGHT NICD4 binds to TACC3 Based on studies in mice, the intracellular domain of NOTCH4, NICD4, binds to transforming acidic coiled-coil protein-3 (TACC3). TACC3 is implicated as a negative regulator of NOTCH4 signaling and may compete with NICD4 binding to RBPJ (Bargo et al. 2010). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 TACC3 Transforming acidic coiled-coil-containing protein 3 ERIC1 Reactome DB_ID: 2160956 UniProt:Q9Y6A5 TACC3 TACC3 ERIC1 FUNCTION Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors (By similarity). Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:21297582, PubMed:23532825). May be involved in the control of cell growth and differentiation. May contribute to cancer (PubMed:14767476).SUBUNIT Interacts with microtubules. Interacts with CKAP5 independently of clathrin. Interacts with CKAP5 and clathrin forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; TACC3 (phosphorylated at Ser-558 by AURKA) and CLTC are proposed to form a composite microtubule interaction surface (PubMed:21297582, PubMed:23918938, PubMed:25596274). Interacts with CCDC100/CEP120. The coiled coil C-terminal region interacts with AH receptor nuclear translocator protein (ARNT) and ARNT2 (By similarity). Interacts with GCN5L2 and PCAF (PubMed:14767476).INDUCTION Up-regulated in various cancer cell lines.SIMILARITY Belongs to the TACC family. UniProt Q9Y6A5 1 EQUAL 838 EQUAL Reactome Database ID Release 81 2160956 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=2160956 Reactome R-HSA-2160956 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-2160956.1 NICD4:TACC3 Reactome DB_ID: 9604678 1 1 Reactome Database ID Release 81 9604678 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=9604678 Reactome R-HSA-9604678 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-9604678.1 Reactome Database ID Release 81 9604675 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=9604675 Reactome R-HSA-9604675 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-9604675.1 Reactome Database ID Release 81 9604323 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=9604323 Reactome R-HSA-9604323 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-9604323.1 22001063 Pubmed 2011 Elongin C is a mediator of Notch4 activity in human renal tubule cells Cummins, Timothy D Mendenhall, Michael D Lowry, Michelle N Korte, Erik A Barati, Michelle T Khundmiri, Syed J Salyer, Sarah A Klein, Jon B Powell, David W Biochim. Biophys. Acta 1814:1748-57 21402876 Pubmed 2011 Trp53 regulates Notch 4 signaling through Mdm2 Sun, Youping Klauzinska, Malgorzata Lake, Robert J Lee, Joseph M Santopietro, Stefania Raafat, Ahmed Salomon, David Callahan, Robert Artavanis-Tsakonas, S J. Cell. Sci. 124:1067-76 Reactome Database ID Release 81 9013694 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=9013694 Reactome R-HSA-9013694 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-9013694.2 18836481 Pubmed 2009 Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis Raafat, A Lawson, S Bargo, S Klauzinska, M Strizzi, L Goldhar, A S Buono, K Salomon, D Vonderhaar, B K Callahan, R Oncogene 28:219-30 11119607 Pubmed 2001 An Epstein-Barr virus protein interacts with Notch Kusano, S Raab-Traub, N J. Virol. 75:384-95 25511451 Pubmed 2015 Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling Qian, Cuijuan Liu, Fuqiang Ye, Bei Zhang, Xin Liang, Yong Yao, J Mol. Cell. Biochem. 401:165-74 8681805 Pubmed 1996 Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene Uyttendaele, H Marazzi, G Wu, G Yan, Q Sassoon, D Kitajewski, J Development 122:2251-9 29057904 Pubmed 2017 The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis Raafat, Ahmed Bargo, Sharon McCurdy, David Callahan, Robert Sci Rep 7:13690 14701863 Pubmed 2004 Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways MacKenzie, Farrell Duriez, Patrick Wong, Fred Noseda, Michela Karsan, Aly J. Biol. Chem. 279:11657-63 16878155 Pubmed 2007 Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis Raafat, A Zoltan-Jones, A Strizzi, L Bargo, S Kimura, K Salomon, D Callahan, R Oncogene 26:662-72 25041739 Pubmed 2015 Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway Li, Yuye Wu, Siyu Pu, Jieying Huang, Xi Zhang, Ping Immunology 144:127-38 11344305 Pubmed 2001 Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium Uyttendaele, H Ho, J Rossant, J Kitajewski, J Proc. Natl. Acad. Sci. U.S.A. 98:5643-8 3023708 Pubmed 1987 Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors Gallahan, D Callahan, R J. Virol. 61:66-74 1312643 Pubmed 1992 Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells Robbins, J Blondel, B J Gallahan, D Callahan, R J. Virol. 66:2594-9