BioPAX pathway converted from "IRE1alpha activates chaperones" in the Reactome database.IRE1alpha activates chaperonesIRE1-alpha is a single-pass transmembrane protein that resides in the endoplasmic reticulum (ER) membrane. The C-terminus of IRE1-alpha is located in the cytosol; the N-terminus is located in the ER lumen. In unstressed cells IRE1-alpha exists in an inactive heterodimeric complex with BiP such that BiP in the ER lumen binds the N-terminal region of IRE1-alpha. Upon accumulation of unfolded proteins in the ER, BiP binds the unfolded protein and the IRE1-alpha:BiP complex dissociates. The dissociated IRE1-alpha then forms homodimers. Initially the luminal N-terminal regions pair. This is followed by trans-autophosphorylation of IRE1-alpha at Ser724 in the cytosolic C-terminal region. The phosphorylation causes a conformational change that allows the dimer to bind ADP, causing a further conformational change to yield back-to-back pairing of the cytosolic C-terminal regions of IRE1-alpha. The fully paired IRE1-alpha homodimer has endoribonuclease activity and cleaves the mRNA encoding Xbp-1. A 26 residue polyribonucleotide is released and the 5' and 3' fragments of the original Xbp-1 mRNA are rejoined. The spliced Xbp-1 message encodes Xbp-1 (S), a potent activator of transcription. Xbp-1 (S) together with the ubiquitous transcription factor NF-Y bind the ER Stress Responsive Element (ERSE) in a number of genes encoding chaperones. Recent data suggest that the IRE1-alpha homodimer can also cleave specific subsets of mRNAs, including the insulin (INS) mRNA in pancreatic beta cells.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37LEFT-TO-RIGHTIRE1:BiP dissociates in response to unfolded proteinIRE1-alpha is a single-pass transmembrane protein with a luminal N-terminus and a cytoplasmic C-terminus. IRE1-alpha is maintained in an inactive state in the Endoplasmic Reticulum (ER) membrane by interaction between the luminal domain of IRE1-alpha and the ATPase domain of BiP within the ER. <br>BiP is a general chaperone that also binds unfolded proteins within the ER. Thus BiP dissociates from IRE1-alpha when chaperone activity is overwhelmed by unfolded proteins in the ER.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:49IRE1:BiPReactome DB_ID: 381202endoplasmic reticulum membraneGENE ONTOLOGYGO:0005789BiPHSPA578 kDa glucose-regulated proteinGRP78Reactome DB_ID: 351315UniProt:P11021 HSPA5HSPA5GRP78FUNCTION Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166).ACTIVITY REGULATION The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains. In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (PubMed:26655470). In contrast, in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates (PubMed:26655470). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP (By similarity). Homooligomerization inactivates participating HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell (By similarity).SUBUNIT Monomer and homooligomer; homooligomerization via the interdomain linker inactivates the chaperone activity and acts as a storage of HSPA5/BiP molecules (By similarity). Interacts with DNAJC1 (via J domain) (By similarity). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity). Interacts with TMEM132A and TRIM21 (PubMed:12699405). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (PubMed:18264092,PubMed:18502753). Interacts with DNAJC10 (PubMed:12411443, PubMed:23769672). Interacts with DNAJB9/ERdj4; leading to recruit HSPA5/BiP to ERN1/IRE1 (By similarity). Interacts with ERN1/IRE1; interaction takes place following interaction with DNAJB9/ERdj4 and leads to inactivate ERN1/IRE1 (By similarity). Interacts with MX1 (By similarity). Interacts with METTL23 (PubMed:23349634). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (PubMed:23990668). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (PubMed:21080038). Interacts with CIPC (PubMed:26657846). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (PubMed:21289099). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (PubMed:26940976). Interacts with MANF; the interaction is direct (PubMed:22637475). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (PubMed:28332555). Interacts with CLU under stressed condition; interaction increases CLU protein stability; facilitates its retrotranslocation and redistribution to the mitochondria; cooperatively suppress stress-induced apoptosis by stabilizing mitochondrial membrane integrity (PubMed:22689054). Interacts with CCDC47 (By similarity). Interacts with CLN3 (Probable). Interacts with KIAA1324; may regulate the function of HSPA5 in apoptosis and cell proliferation (PubMed:26045166). Interacts with CASP7 (PubMed:26045166).INDUCTION By endoplasmic reticulum stress.DOMAIN The interdomain linker regulates the chaperone activity by mediating the formation of homooligomers. Homooligomers are formed by engagement of the interdomain linker of one HSPA5/BiP molecule as a typical substrate of an adjacent HSPA5/BiP molecule. HSPA5/BiP oligomerization inactivates participating HSPA5/BiP protomers. HSPA5/BiP oligomers probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell. When the levels of unfolded proteins rise, cells can rapidly break up these oligomers to make active monomers.PTM AMPylated by FICD (PubMed:25601083). In unstressed cells, AMPylation at Thr-518 by FICD inactivates the chaperome activity: AMPylated form is locked in a relatively inert state and only weakly stimulated by J domain-containing proteins (By similarity). In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity (By similarity).DISEASE Autoantigen in rheumatoid arthritis.SIMILARITY Belongs to the heat shock protein 70 family.CAUTION AMPylation was initially reported to take place at Ser-365 and Thr-366 in vitro, and promote activation of HSPA5/BiP (PubMed:25601083). However, it was later shown that AMPylation takes place at Thr-518 and leads to inactivation of HSPA5/BiP.Homo sapiensNCBI Taxonomy9606UniProtP1102119EQUAL654EQUALReactome Database ID Release 75351315Database 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=351315ReactomeR-HSA-3513151Reactome 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-351315.1Reactomehttp://www.reactome.org1ERN1IRE1Reactome DB_ID: 381076UniProt:O75460 ERN1ERN1IRE1FUNCTION Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875, PubMed:28128204). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A (PubMed:21884936, PubMed:28067262).ACTIVITY REGULATION The kinase domain is activated by trans-autophosphorylation following homodimerization (PubMed:12637535, PubMed:9637683). Kinase activity is required for activation of the endoribonuclease domain (PubMed:12637535, PubMed:9637683). Endoribonuclease activity is specifically inhibited by hydroxy-aryl-aldehydes (HAA) (By similarity).SUBUNIT Monomer (PubMed:29198525, PubMed:16973740). Homodimer; disulfide-linked; homodimerization takes place in response to endoplasmic reticulum stress and promotes activation of the kinase and endoribonuclease activities (PubMed:12637535, PubMed:24508390, PubMed:16973740, PubMed:21317875). Dimer formation is driven by hydrophobic interactions within the N-terminal luminal domains and stabilized by disulfide bridges (PubMed:12637535). Interacts (via the luminal region) with DNAJB9/ERdj4; interaction takes place in unstressed cells and promotes recruitment of HSPA5/BiP (PubMed:29198525). Interacts (via the luminal region) with HSPA5/BiP; HSPA5/BiP is a negative regulator of the unfolded protein response (UPR) that prevents homodimerization of ERN1/IRE1 and subsequent activation of the protein (PubMed:12637535, PubMed:29198525). Interacts with PDIA6, a negative regulator of the UPR; the interaction is direct and disrupts homodimerization (PubMed:24508390). Interacts with DAB2IP (via PH domain); the interaction occurs in a endoplasmic reticulum stress-induced dependent manner and is required for subsequent recruitment of TRAF2 to ERN1/IRE1 (By similarity). Interacts with TAOK3 and TRAF2 (PubMed:11278723). Interacts with RNF13 (PubMed:23378536). Interacts with LACC1 (PubMed:31875558). Interacts (when unphosphorylated) with DDRGK1; interaction is dependent on UFM1 and takes place in response to endoplasmic reticulum stress, regulating ERN1/IRE1-alpha stability (PubMed:28128204).TISSUE SPECIFICITY Ubiquitously expressed. High levels observed in pancreatic tissue.PTM Autophosphorylated following homodimerization. Autophosphorylation promotes activation of the endoribonuclease domain.PTM ADP-ribosylated by PARP16 upon ER stress, which increases both kinase and endonuclease activities.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.UniProtO7546019EQUAL977EQUALReactome Database ID Release 75381076Database 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=381076ReactomeR-HSA-3810761Reactome 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-381076.11Reactome Database ID Release 75381202Database 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=381202ReactomeR-HSA-3812021Reactome 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-381202.1unfolded proteinReactome DB_ID: 381130endoplasmic reticulum lumenGENE ONTOLOGYGO:0005788Reactome Database ID Release 75381130Database 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=381130ReactomeR-HSA-3811302Reactome 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-381130.2ChEBI36080additional informationMIMI:0361BiP:Unfolded ProteinReactome DB_ID: 381062BiPHSPA578 kDa glucose-regulated proteinGRP78Reactome DB_ID: 38719019EQUAL654EQUALReactome Database ID Release 75387190Database 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=387190ReactomeR-HSA-3871901Reactome 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-387190.111Reactome Database ID Release 75381062Database 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=381062ReactomeR-HSA-3810621Reactome 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-381062.1Reactome Database ID Release 75381217Database 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=381217ReactomeR-HSA-3812171Reactome 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-381217.116973740Pubmed2006The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein responseZhou, JLiu, CYBack, SHClark, RLPeisach, DXu, ZKaufman, RJProc Natl Acad Sci U S A 103:14343-811897784Pubmed2002The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domainLiu, CYWong, HNSchauerte, JAKaufman, RJJ Biol Chem 277:18346-5619538957Pubmed2009Activation of mammalian IRE1alpha upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteinsOikawa, DKimata, YKohno, KIwawaki, TExp Cell Res 315:2496-504LEFT-TO-RIGHTIRE1 binds IRE1 forming dimerThe dissociation of the IRE1-alpha:BiP heterodimer liberates IRE1-alpha, which forms homodimers. Dimer formation is initiated by interaction between the N-terminal, luminal domains.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:492IRE1 dimerReactome DB_ID: 3812002Reactome Database ID Release 75381200Database 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=381200ReactomeR-HSA-3812001Reactome 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-381200.1Reactome Database ID Release 75381109Database 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=381109ReactomeR-HSA-3811091Reactome 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-381109.110835430Pubmed2000Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulumLiu, CYSchröder, MartinKaufman, RJJ Biol Chem 275:24881-516365312Pubmed2005On the mechanism of sensing unfolded protein in the endoplasmic reticulumCredle, JJFiner-Moore, JSPapa, FRStroud, RMWalter, PProc Natl Acad Sci U S A 102:18773-8411069889Pubmed2000The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein responseTirasophon, WLee, KCallaghan, BWelihinda, AKaufman, RJGenes Dev 14:2725-3618191223Pubmed2008Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicingLee, KPDey, MNeculai, DCao, CDever, TESicheri, FCell 132:89-100LEFT-TO-RIGHT2.7.11IRE1 dimer autophosphorylatesDimerization of the N-terminal luminal regions of IRE1-alpha brings the cytosolic C-terminal regions in proximity. The C-terminal region possesses kinase activity and the homodimer trans-autophosphorylates. From homology with Saccharomyces IRE1-alpha the phosphorylation of human IRE1-alpha is believed to be at Ser724.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:49ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592cytosolGENE ONTOLOGYGO:0005829ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 75113592Database 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=113592ReactomeR-ALL-1135924Reactome 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-113592.4COMPOUNDC000022ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7529370Database 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=29370ReactomeR-ALL-293704Reactome 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-29370.4COMPOUNDC000082p-S724-IRE1 dimerReactome DB_ID: 381154p-S724-ERN1IRE1 (phosphorylated)Reactome DB_ID: 381029724EQUALO-phospho-L-serineMODMOD:0004619EQUAL977EQUALReactome Database ID Release 75381029Database 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=381029ReactomeR-HSA-3810291Reactome 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-381029.12Reactome Database ID Release 75381154Database 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=381154ReactomeR-HSA-3811541Reactome 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-381154.1ACTIVATIONGENE ONTOLOGYGO:0004674gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 75381048Database 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=381048Reactome Database ID Release 75381091Database 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=381091ReactomeR-HSA-3810911Reactome 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-381091.19637683Pubmed1998A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cellsTirasophon, WWelihinda, AAKaufman, RJGenes Dev 12:1812-24LEFT-TO-RIGHTPhosphorylated IRE1 dimer binds ADPPhosphorylation of the C-terminal region causes a loop in the C-terminus to change position, enabling access to an ADP-binding pocket. Phosphorylated IRE1-alpha dimers bind ADP in preference to ATP.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:492p-S724-IRE1 dimer:ADPReactome DB_ID: 3810781ADPADP(3-)Reactome DB_ID: 211606Reactome Database ID Release 75211606Database 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=211606ReactomeR-ALL-2116063Reactome 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-211606.32Reactome Database ID Release 75381078Database 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=381078ReactomeR-HSA-3810781Reactome 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-381078.1Reactome Database ID Release 75381116Database 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=381116ReactomeR-HSA-3811161Reactome 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-381116.1LEFT-TO-RIGHTIRE1alpha hydrolyzes Xbp1 mRNA and Xbp1 mRNA is splicedPhosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. The IRE1-alpha homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human ligase has not been identified. The cleavage and ligation leads to a frameshift in the Xbp-1 mRNA which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factorAuthored: May, B, 2009-06-03Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-03Xbp1 mRNA (unspliced)Reactome DB_ID: 425921ENSEMBL_Homo_sapiens_TRANSCRIPT:ENST00000216037 Xbp1 mRNA (unspliced)Xbp1 mRNA (unspliced)XBP1ENSEMBLENST00000216037Reactome Database ID Release 75425921Database 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=425921ReactomeR-HSA-4259211Reactome 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-425921.1Xbp1 mRNA (spliced)Reactome DB_ID: 425925ENSEMBL_Homo_sapiens_TRANSCRIPT:ENST00000344347 Xbp1 mRNA (spliced)Xbp1 mRNA (spliced)XBP1ENSEMBLENST00000344347Reactome Database ID Release 75425925Database 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=425925ReactomeR-HSA-4259251Reactome 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-425925.1ACTIVATIONGENE ONTOLOGYGO:0004521Reactome Database ID Release 75381180Database 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=381180Reactome Database ID Release 75425923Database 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=425923ReactomeR-HSA-4259232Reactome 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-425923.211779464Pubmed2001XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factorYoshida, HMatsui, TYamamoto, AOkada, TMori, KCell 107:881-9119622636Pubmed2009Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein responseUemura, AOku, MMori, KYoshida, HJ Cell Sci 122:2877-8617026957Pubmed2006Analysis of the XBP1 splicing mechanism using endoplasmic reticulum stress-indicatorsIwawaki, TAkai, RBiochem Biophys Res Commun 350:709-1518242182Pubmed2008RNase domains determine the functional difference between IRE1alpha and IRE1betaImagawa, YHosoda, ASasaka, STsuru, AKohno, KFEBS Lett 582:656-60LEFT-TO-RIGHTXBP(S) mRNA is translated and XBP1(S) translocates to the nucleusPhosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. In particular, the homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human enzyme has not been identified. The cleavage and ligation leads to a frameshift which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factor.<br>The ribonuclease activity of IRE1-alpha also degrades subsets of mRNAs in the vicinity of the ER membrane, thereby reducing the amount of protein entering the ER.<br>Xbp-1 mRNA that has been cleaved by IRE1-alpha encodes a 40 kd protein designated Xbp-1 (S). Xbp-1 (S) is a potent bZIP transcription factor that transits from the cytosol to the nucleus and binds the sequence CCACG in the ER Stress Responsive Element (ERSE).Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:49XBP1-2XBP1(S)XBP1 isoform 2XBP-1SReactome DB_ID: 381096nucleoplasmGENE ONTOLOGYGO:0005654UniProt:P17861-2 XBP1XBP1TREB5XBP2FUNCTION Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland (By similarity). Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins (PubMed:11460154). Modulates the cellular response to ER stress in a PIK3R-dependent manner (PubMed:20348923). Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes (PubMed:8349596). Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention (By similarity).SUBUNIT Isoform 2 interacts with SIRT1. Isoform 2 interacts with PIK3R1 and PIK3R2; the interactions are direct and induce translocation of XBP1 isoform 2 into the nucleus and the unfolded protein response (UPR) XBP1-dependent target genes activation in a ER stress- and/or insulin-dependent but PI3K-independent manner. Isoform 2 interacts with FOXO1; the interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway in hepatocytes (By similarity). Isoform 1 interacts with HM13 (PubMed:25239945). Isoform 1 interacts with RNF139; the interaction induces ubiquitination and degradation of isoform 1 (PubMed:25239945). Isoform 1 interacts (via luminal domain) with DERL1; the interaction obviates the need for ectodomain shedding prior HM13/SPP-mediated XBP1 isoform 1 cleavage (PubMed:25239945). Isoform 1 interacts with isoform 2; the interaction sequesters isoform 2 from the nucleus and enhances isoform 2 degradation in the cytoplasm (PubMed:16461360, PubMed:25239945). Isoform 1 interacts with HDAC3 and AKT1; the interactions occur in endothelial cell (EC) under disturbed flow (PubMed:25190803). Isoform 1 interacts with the oncoprotein FOS (PubMed:1903538). Isoform 2 interacts with ATF6; the interaction occurs in a ER stress-dependent manner and is required for DNA binding to the unfolded protein response element (UPRE) (PubMed:17765680). Isoform 2 interacts with PIK3R1; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus and the unfolded protein response (UPR) XBP1-dependent target genes activation in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348923).TISSUE SPECIFICITY Expressed in plasma cells in rheumatoid synovium (PubMed:11460154). Over-expressed in primary breast cancer and metastatic breast cancer cells (PubMed:25280941). Isoform 1 and isoform 2 are expressed at higher level in proliferating as compared to confluent quiescent endothelial cells (PubMed:19416856).INDUCTION Isoform 1 is up-regulated at the recovery phase of the endoplasmic reticulum (ER) stress response and isoform 2 is up-regulated early during the ER stress response and gradually decreased at later phase of ER stress (PubMed:16461360). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (at protein level) (PubMed:19416856). Down-regulated by the B-cell-specific transcription factor PAX5 (PubMed:8627152). Up-regulated by interleukin IL-6 in myeloma cells (PubMed:10375612). Up-regulated during plasma-cell differentiation, either through the CD40 receptor signaling pathway or mitogens such as lipopolysaccharide (LPS) (PubMed:11460154). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803). Isoform 2 is up-regulated early during the ER stress response in a ATF6-dependent manner (PubMed:11779464, PubMed:17110785, PubMed:16461360). Isoform 2 is up-regulated by endostatin in a ERN1-dependent manner (PubMed:23184933). Isoform 2 is transiently up-regulated by the mitogenic vascular endothelial growth factor (VEGF) in endothelial cells (PubMed:23529610).DOMAIN Isoform 1 and isoform 2 N-terminus domains are necessary for nuclear localization targeting. Isoform 1 C-terminus domain confers localization to the cytoplasm and is sufficient to impose rapid degradation (By similarity). Isoform 1 transmembrane signal-anchor domain is necessary for its own mRNA to be recruited to the endoplasmic reticulum (ER) which will undergo unconventional ERN1-dependent splicing in response to ER stress (PubMed:19394296, PubMed:21233347). Isoform 1 N-terminus and C-terminus regions are necessary for DNA-binding and weak transcriptional activity, respectively. Isoform 2 N-terminus and C-terminus regions are necessary for DNA-binding and strong transcriptional activity upon ER stress, respectively (PubMed:11779464, PubMed:8657566). Isoform 2 C-terminus region contains a nuclear exclusion signal (NES) at positions 186 through 208. Isoform 2 C-terminus region contains a degradation domain at positions 209 through 261 (PubMed:16461360).PTM X-box-binding protein 1, cytoplasmic form and luminal form are produced by intramembrane proteolytic cleavage of ER membrane-anchored isoform 1 triggered by HM13/SPP in a DERL1-RNF139-dependent and VCP/p97-independent manner. X-box-binding protein 1, luminal form is ubiquitinated leading to proteasomal degradation (PubMed:25239945).SIMILARITY Belongs to the bZIP family.UniProt IsoformP17861-21EQUAL261EQUALReactome Database ID Release 75381096Database 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=381096ReactomeR-HSA-3810961Reactome 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-381096.1Reactome Database ID Release 75381203Database 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=381203ReactomeR-HSA-3812031Reactome 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-381203.18657566Pubmed1996The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT coreClauss, IMChu, MZhao, JLGlimcher, LHNucleic Acids Res 24:1855-6416461360Pubmed2006pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress responseYoshida, HOku, MSuzuki, MMori, KJ Cell Biol 172:565-75XBP1(S) activates chaperone genesXbp-1 (S) binds the sequence CCACG in ER Stress Responsive Elements (ERSE, consensus sequence CCAAT (N)9 CCACG) located upstream from many genes. The ubiquitous transcription factor NF-Y, a heterotrimer, binds the CCAAT portion of the ERSE and together the IRE1-alpha: NF-Y complex activates transcription of a set of chaperone genes including DNAJB9, EDEM, RAMP4, p58IPK, and others. This results in an increase in protein folding activity in the ER.Authored: May, B, 2009-06-02 00:51:49Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2009-06-02 00:51:49LEFT-TO-RIGHTExpression of ACADVLThe ACADVL gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13ACADVL geneReactome DB_ID: 5642270ENSEMBL:ENSG00000072778 ACADVLACADVLVLCADENSEMBLENSG00000072778Reactome Database ID Release 755642270Database 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=5642270ReactomeR-HSA-56422701Reactome 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-5642270.1VLCADACADVLAcyl-CoA dehydrogenase, very-long-chain specific, mitochondrial precursor Reactome DB_ID: 49495mitochondrial matrixGENE ONTOLOGYGO:0005759UniProt:P49748 ACADVLACADVLVLCADFUNCTION Active toward esters of long-chain and very long chain fatty acids such as palmitoyl-CoA, myristoyl-CoA and stearoyl-CoA. Can accommodate substrate acyl chain lengths as long as 24 carbons, but shows little activity for substrates of less than 12 carbons.PATHWAY Lipid metabolism; mitochondrial fatty acid beta-oxidation.SUBUNIT Homodimer.PTM S-nitrosylation at Cys-237 in liver improves catalytic efficiency.MISCELLANEOUS A number of straight-chain acyl-CoA dehydrogenases of different substrate specificities are present in mammalian tissues.SIMILARITY Belongs to the acyl-CoA dehydrogenase family.UniProtP4974841EQUAL655EQUALReactome Database ID Release 7549495Database 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=49495ReactomeR-HSA-494951Reactome 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-49495.1Reactome Database ID Release 751791069Database 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=1791069ReactomeR-HSA-17910694Reactome 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-1791069.416539657Pubmed2006XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cellsKakiuchi, CIshiwata, MHayashi, AKato, TJ Neurochem 97:545-55ACTIVATIONReactome Database ID Release 751791189Database 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=1791189ReactomeR-HSA-17911891Reactome 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-1791189.1LEFT-TO-RIGHTExpression of ADD1 (Adducin alpha)The ADD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13ADD1 geneReactome DB_ID: 5642279ENSEMBL:ENSG00000087274 ADD1ADD1ADDAENSEMBLENSG00000087274Reactome Database ID Release 755642279Database 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=5642279ReactomeR-HSA-56422791Reactome 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-5642279.1ADD1Adducin alphaAlpha adducinReactome DB_ID: 201623UniProt:P35611 ADD1ADD1ADDAFUNCTION Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to calmodulin.SUBUNIT Heterodimer of an alpha and a beta subunit or an alpha and a gamma subunit.TISSUE SPECIFICITY Expressed in all tissues. Found in much higher levels in reticulocytes than the beta subunit.DOMAIN Each subunit is comprised of three regions: a NH2-terminal protease-resistant globular head region, a short connecting subdomain, and a protease-sensitive tail region.SIMILARITY Belongs to the aldolase class II family. Adducin subfamily.UniProtP356111EQUAL737EQUALReactome Database ID Release 75201623Database 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=201623ReactomeR-HSA-2016231Reactome 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-201623.1Reactome Database ID Release 751791076Database 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=1791076ReactomeR-HSA-17910764Reactome 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-1791076.4ACTIVATIONReactome Database ID Release 751791249Database 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=1791249ReactomeR-HSA-17912491Reactome 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-1791249.1LEFT-TO-RIGHTExpression of ATP6VOD1The ATP6VOD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13ATP6V0D1 geneReactome DB_ID: 5642224ENSEMBL:ENSG00000159720 ATPV0D1ATPV0D1ATP6V0D1ATP6DVPATPDENSEMBLENSG00000159720Reactome Database ID Release 755642224Database 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=5642224ReactomeR-HSA-56422241Reactome 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-5642224.1ATP6V0D1Reactome DB_ID: 912592endosome membraneGENE ONTOLOGYGO:0010008UniProt:P61421 ATP6V0D1ATP6V0D1ATP6DVPATPDFUNCTION Subunit of the integral membrane V0 complex of the lysosomal proton-transporting V-type ATPase (v-ATPase) (PubMed:28296633, PubMed:30374053). V-ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells, thus providing most of the energy required for transport processes in the vacuolar system (PubMed:30374053). May play a role in coupling of proton transport and ATP hydrolysis (By similarity). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium (By similarity).SUBUNIT V-ATPase is a heteromultimeric enzyme composed of a peripheral catalytic V1 complex (components A to H) attached to an integral membrane V0 proton pore complex (components: a, c, c', c'' and d) (By similarity). Interacts with ATP6AP2; ATP6AP2 is a v-ATPase accessory protein and the interaction promotes v-ATPase complex assembly (PubMed:30374053). Interacts with TMEM9; TMEM9 is a v-ATPase assembly regulator and the interaction induces the interaction with ATP6AP2 (PubMed:30374053). Interacts with PIP4P1 (PubMed:29644770).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the V-ATPase V0D/AC39 subunit family.UniProtP614211EQUAL351EQUALReactome Database ID Release 75912592Database 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=912592ReactomeR-HSA-9125921Reactome 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-912592.1Reactome Database ID Release 751791184Database 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=1791184ReactomeR-HSA-17911844Reactome 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-1791184.4ACTIVATIONReactome Database ID Release 751791242Database 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=1791242ReactomeR-HSA-17912421Reactome 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-1791242.1LEFT-TO-RIGHTExpression of C19orf10The C19orf10 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13C19orf10 geneReactome DB_ID: 5642292ENSEMBL:ENSG00000074842 C19orf10C19orf10MYDGFIL25ENSEMBLENSG00000074842Reactome Database ID Release 755642292Database 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=5642292ReactomeR-HSA-56422921Reactome 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-5642292.1C19orf10UPF0556 protein C19orf10CS010_HUMANReactome DB_ID: 535584UniProt:Q969H8 MYDGFMYDGFC19orf10FUNCTION Bone marrow-derived monocyte and paracrine-acting protein that promotes cardiac myocyte survival and adaptive angiogenesis for cardiac protection and/or repair after myocardial infarction (MI). Stimulates endothelial cell proliferation through a MAPK1/3-, STAT3- and CCND1-mediated signaling pathway. Inhibits cardiac myocyte apoptosis in a PI3K/AKT-dependent signaling pathway (By similarity). Involved in endothelial cell proliferation and angiogenesis (PubMed:25581518).TISSUE SPECIFICITY Expressed in eosinophils (at protein level) (PubMed:29954947). Expressed in bone marrow cells (PubMed:25581518). Expressed in synovial tissue. Found in synovial fluid of patients with arthropaties (PubMed:17362502).INDUCTION Up-regulated in response to myocardial infarction (MI).SIMILARITY Belongs to the MYDGF family.CAUTION Was originally thought to signal lymphoid cells to proliferate via thymic shared antigen 1 (PubMed:11714798). This work was later retracted (PubMed:12538725).CAUTION It has been reported that MYDGF is secreted into blood plasma and localized to the endoplasmic reticulum-Golgi intermediate compartment (PubMed:17362502, PubMed:25581518). However, another report shows resident localization to the endoplasmic reticulum and Golgi apparatus and secretion when the two most C-terminal residues of the RTEL motif are abolished (PubMed:29954947).UniProtQ969H832EQUAL173EQUALReactome Database ID Release 75535584Database 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=535584ReactomeR-HSA-5355841Reactome 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-535584.1Reactome Database ID Release 751791102Database 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=1791102ReactomeR-HSA-17911024Reactome 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-1791102.4ACTIVATIONReactome Database ID Release 751791220Database 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=1791220ReactomeR-HSA-17912201Reactome 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-1791220.1LEFT-TO-RIGHTExpression of CTDSP2The CTDSP2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13CTDSP2 geneReactome DB_ID: 5642237ENSEMBL:ENSG00000175215 CTDSP2CTDSP2NIF2OS4SCP2ENSEMBLENSG00000175215Reactome Database ID Release 755642237Database 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=5642237ReactomeR-HSA-56422371Reactome 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-5642237.1CTDSP2Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2CTDS2_HUMANReactome DB_ID: 535488UniProt:O14595 CTDSP2CTDSP2NIF2OS4SCP2FUNCTION Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation. Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. May contribute to the development of sarcomas.SUBUNIT Monomer (By similarity). Interacts with REST.TISSUE SPECIFICITY Expression is restricted to non-neuronal tissues. Highest expression in pancreas and lowest in liver.INDUCTION In primary sarcomas.UniProtO145951EQUAL271EQUALReactome Database ID Release 75535488Database 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=535488ReactomeR-HSA-5354881Reactome 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-535488.1Reactome Database ID Release 751791130Database 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=1791130ReactomeR-HSA-17911303Reactome 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-1791130.3ACTIVATIONReactome Database ID Release 751791226Database 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=1791226ReactomeR-HSA-17912261Reactome 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-1791226.1LEFT-TO-RIGHTExpression of CXXC1The CXXC1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13CXXC1 geneReactome DB_ID: 5642305ENSEMBL:ENSG00000154832 CXXC1CXXC1CFP1CGBPPCCX1PHF18ENSEMBLENSG00000154832Reactome Database ID Release 755642305Database 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=5642305ReactomeR-HSA-56423051Reactome 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-5642305.1CXXC1CpG-binding proteinCXXC1_HUMANReactome DB_ID: 535610UniProt:Q9P0U4 CXXC1CXXC1CFP1CGBPPCCX1PHF18FUNCTION Transcriptional activator that exhibits a unique DNA binding specificity for CpG unmethylated motifs with a preference for CpGG.SUBUNIT Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1 HCFC1 and DPY30. Interacts with SETD1A. Interacts with ZNF335. Interacts with PRDM9; this interaction does not link PRDM9-activated recombination hotspot sites with DSB machinery and is not required for the hotspot recognition pathway. Interacts with histone H3K4me3 (By similarity).TISSUE SPECIFICITY Ubiquitous.DOMAIN The acidic domain carries the potential to activate transcription.PTM May be regulated by proteolysis.UniProtQ9P0U41EQUAL656EQUALReactome Database ID Release 75535610Database 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=535610ReactomeR-HSA-5356101Reactome 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-535610.1Reactome Database ID Release 751791158Database 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=1791158ReactomeR-HSA-17911583Reactome 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-1791158.3ACTIVATIONReactome Database ID Release 751791192Database 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=1791192ReactomeR-HSA-17911921Reactome 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-1791192.1LEFT-TO-RIGHTExpression of Cullin-7The Cullin-7 (CUL7) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13CUL7 geneReactome DB_ID: 5642255ENSEMBL:ENSG00000044090 CUL7CUL7KIAA0076ENSEMBLENSG00000044090Reactome Database ID Release 755642255Database 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=5642255ReactomeR-HSA-56422551Reactome 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-5642255.1CUL7Cullin-7CUL7_HUMANReactome DB_ID: 535534UniProt:Q14999 CUL7CUL7KIAA0076FUNCTION Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediates the ubiquitination of target proteins. Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695). Interaction with CUL9 is required to inhibit CUL9 activity and ubiquitination of BIRC5 (PubMed:24793696). Core component of a Cul7-RING ubiquitin-protein ligase with FBXW8, which mediates ubiquitination and consequent degradation of target proteins such as GORASP1, IRS1 and MAP4K1/HPK1 (PubMed:21572988, PubMed:24362026). Ubiquitination of GORASP1 regulates Golgi morphogenesis and dendrite patterning in brain (PubMed:21572988). Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2) (PubMed:18498745). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation (PubMed:24362026). Acts as a regulator in trophoblast cell epithelial-mesenchymal transition and placental development (PubMed:20139075). Does not promote polyubiquitination and proteasomal degradation of p53/TP53 (PubMed:16547496, PubMed:17332328). While the Cul7-RING(FBXW8) and the 3M complexes are associated and involved in common processes, CUL7 and the Cul7-RING(FBXW8) complex may be have additional functions.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Part of a Cul7-RING complex consisting of CUL7, RBX1, SKP1 and FBXW8. Interacts with a complex of SKP1 and FBXW8, but not with SKP1 alone. Interacts with CUL9; leading to inhibit CUL9 activity. Interacts with FBXW8; interaction is mutually exclusive of binding to CUL9 or p53/TP53. Interacts with p53/TP53; the interaction preferentially involves tetrameric and dimeric p53/TP53. The CUL7-CUL9 heterodimer seems to interact specifically with p53/TP53. Interacts with CUL1; the interactions seems to be mediated by FBXW8. Interacts with OBSL1. Interacts (as part of the 3M complex) with HDAC4 and HDAC5; it is negatively regulated by ANKRA2.SUBUNIT (Microbial infection) Interacts with SV40 Large T antigen; this interaction seems to inhibit CUL7.TISSUE SPECIFICITY Highly expressed in fetal kidney and adult skeletal muscle. Also abundant in fetal brain, as well as in adult pancreas, kidney, placenta and heart. Detected in trophoblasts, lymphoblasts, osteoblasts, chondrocytes and skin fibroblasts.DEVELOPMENTAL STAGE Highly expressed in invasive placental villi during first trimester.PTM According to a report, may not be neddylated despite the conserved consensus site for neddylation at Lys-1576.SIMILARITY Belongs to the cullin family.UniProtQ149991EQUAL1698EQUALReactome Database ID Release 75535534Database 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=535534ReactomeR-HSA-5355341Reactome 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-535534.1Reactome Database ID Release 751791058Database 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=1791058ReactomeR-HSA-17910584Reactome 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-1791058.4ACTIVATIONReactome Database ID Release 751791241Database 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=1791241ReactomeR-HSA-17912411Reactome 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-1791241.1LEFT-TO-RIGHTExpression of DCTN1The DCTN1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13DCTN1 geneReactome DB_ID: 5642226ENSEMBL:ENSG00000204843 DCTN1DCTN1ENSEMBLENSG00000204843Reactome Database ID Release 755642226Database 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=5642226ReactomeR-HSA-56422261Reactome 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-5642226.1DCTN1Dynactin subunit 1DCTN1_HUMANp150-gluedReactome DB_ID: 535580UniProt:Q14203 DCTN1DCTN1FUNCTION Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and enhancing dynein processivity (the ability to move along a microtubule for a long distance without falling off the track). Can also act as a brake to slow the dynein motor during motility along the microtubule (PubMed:25185702). Can regulate microtubule stability by promoting microtubule formation, nucleation and polymerization and by inhibiting microtubule catastrophe in neurons. Inhibits microtubule catastrophe by binding both to microtubules and to tubulin, leading to enhanced microtubule stability along the axon (PubMed:23874158). Plays a role in metaphase spindle orientation (PubMed:22327364). Plays a role in centriole cohesion and subdistal appendage organization and function. Its recruitment to the centriole in a KIF3A-dependent manner is essential for the maintenance of centriole cohesion and the formation of subdistal appendage. Also required for microtubule anchoring at the mother centriole (PubMed:23386061). Plays a role in primary cilia formation (PubMed:25774020).SUBUNIT Monomer and homodimer (PubMed:23874158). Dynactin is a large macromolecular complex of at least 10 components; p150(glued) binds directly to microtubules and to cytoplasmic dynein. Interacts with the C-terminus of MAPRE1, MAPRE2 and MAPRE3. Interacts (via C-terminus) with SNX6. Interacts with CLN3, DYNAP, ECPAS and FBXL5. Interacts with MISP; this interaction regulates its distribution at the cell cortex. Interacts with CEP131. Interacts with CEP126 (PubMed:24867236). Interacts with CLIP1 (PubMed:17828275, PubMed:17828277, PubMed:26972003, PubMed:20679239). Interacts with dynein intermediate chain and dynein heavy chain (PubMed:25185702). Interacts with PLK1 (via POLO-box domain) (PubMed:20679239). Interacts with TBCB (PubMed:22777741). Binds preferentially to tyrosinated microtubules than to detyrosinated microtubules (PubMed:26972003, PubMed:26968983). Interacts with PARD6A (PubMed:20719959). Interacts with HPS6 (PubMed:25189619). Interacts with KIF3A. Interacts with BICD2 (By similarity). Interacts with DST (isoform 9) (By similarity). Interacts with DST (isoform 1) (By similarity). Identified in a complex with MREG and RILP (By similarity). Interacts with BCCIP (isoform 2/alpha) (PubMed:28394342). Interacts with DCDC1 (PubMed:22159412). Interacts with AKNA (By similarity). Interacts with DYNC1I2 (By similarity).TISSUE SPECIFICITY Brain.DOMAIN The CAP-Gly domain is essential for interactions with microtubules and its binding partners and for its motion along the microtubules. Essential for its preferential binding to tyrosinated microtubules and for promoting the sustained interaction of the dynein motor with microtubules.PTM Ubiquitinated by a SCF complex containing FBXL5, leading to its degradation by the proteasome.PTM Phosphorylation by SLK at Thr-145, Thr-146 and Thr-147 targets DCTN1 to the centrosome. It is uncertain if SLK phosphorylates all three threonines or one or two of them. PLK1-mediated phosphorylation at Ser-179 is essential for its localization in the nuclear envelope, promotes its dissociation from microtubules during early mitosis and positively regulates nuclear envelope breakdown during prophase.SIMILARITY Belongs to the dynactin 150 kDa subunit family.UniProtQ142031EQUAL1278EQUALReactome Database ID Release 75535580Database 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=535580ReactomeR-HSA-5355802Reactome 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-535580.2Reactome Database ID Release 751791092Database 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=1791092ReactomeR-HSA-17910924Reactome 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-1791092.4ACTIVATIONReactome Database ID Release 751791204Database 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=1791204ReactomeR-HSA-17912041Reactome 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-1791204.1LEFT-TO-RIGHTExpression of DDX11The DDX11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13DDX11 geneReactome DB_ID: 5642245ENSEMBL:ENSG00000013573 DDX11DDX11CHL1CHLR1KRG2ENSEMBLENSG00000013573Reactome Database ID Release 755642245Database 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=5642245ReactomeR-HSA-56422451Reactome 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-5642245.1DDX11Probable ATP-dependent RNA helicase DDX11DDX11_HUMANReactome DB_ID: 535492UniProt:Q96FC9 DDX11DDX11CHL1CHLR1KRG2FUNCTION DNA-dependent ATPase and ATP-dependent DNA helicase that participates in various functions in genomic stability, including DNA replication, DNA repair and heterochromatin organization as well as in ribosomal RNA synthesis (PubMed:10648783, PubMed:21854770, PubMed:23797032, PubMed:26089203, PubMed:26503245). Its double-stranded DNA helicase activity requires either a minimal 5'-single-stranded tail length of approximately 15 nt (flap substrates) or 10 nt length single-stranded gapped DNA substrates of a partial duplex DNA structure for helicase loading and translocation along DNA in a 5' to 3' direction (PubMed:18499658, PubMed:22102414). The helicase activity is capable of displacing duplex regions up to 100 bp, which can be extended up to 500 bp by the replication protein A (RPA) or the cohesion CTF18-replication factor C (Ctf18-RFC) complex activities (PubMed:18499658). Shows also ATPase- and helicase activities on substrates that mimic key DNA intermediates of replication, repair and homologous recombination reactions, including forked duplex, anti-parallel G-quadruplex and three-stranded D-loop DNA molecules (PubMed:22102414, PubMed:26503245). Plays a role in DNA double-strand break (DSB) repair at the DNA replication fork during DNA replication recovery from DNA damage (PubMed:23797032). Recruited with TIMELESS factor upon DNA-replication stress response at DNA replication fork to preserve replication fork progression, and hence ensure DNA replication fidelity (PubMed:26503245). Cooperates also with TIMELESS factor during DNA replication to regulate proper sister chromatid cohesion and mitotic chromosome segregation (PubMed:17105772, PubMed:18499658, PubMed:20124417, PubMed:23116066, PubMed:23797032). Stimulates 5'-single-stranded DNA flap endonuclease activity of FEN1 in an ATP- and helicase-independent manner; and hence it may contribute in Okazaki fragment processing at DNA replication fork during lagging strand DNA synthesis (PubMed:18499658). Its ability to function at DNA replication fork is modulated by its binding to long non-coding RNA (lncRNA) cohesion regulator non-coding RNA DDX11-AS1/CONCR, which is able to increase both DDX11 ATPase activity and binding to DNA replicating regions (PubMed:27477908). Plays also a role in heterochromatin organization (PubMed:21854770). Involved in rRNA transcription activation through binding to active hypomethylated rDNA gene loci by recruiting UBTF and the RNA polymerase Pol I transcriptional machinery (PubMed:26089203). Plays a role in embryonic development and prevention of aneuploidy (By similarity). Involved in melanoma cell proliferation and survival (PubMed:23116066). Associates with chromatin at DNA replication fork regions (PubMed:27477908). Binds to single- and double-stranded DNAs (PubMed:9013641, PubMed:18499658, PubMed:22102414).FUNCTION (Microbial infection) Required for bovine papillomavirus type 1 regulatory protein E2 loading onto mitotic chromosomes during DNA replication for the viral genome to be maintained and segregated.ACTIVITY REGULATION ATPase activity is stimulated by high magnesium salt levels (up to a 0.1 M), and potassium salts (glutamate, chloride or acetate) are more effective than the corresponding sodium salts (PubMed:10648783, PubMed:18499658). ATPase activity is enhanced by the long non-coding RNA (lncRNA) cohesion regulator noncoding RNA (CONCR) (PubMed:27477908). Double-stranded DNA helicase activity is maximal with magnesium ions at low concentrations (0.5-1 mM) whereas is markedly inhibited at higher levels (5 mM and above) (PubMed:10648783, PubMed:18499658). Double-stranded DNA helicase activity is stimulated by 25-50 mM potassium acetate, stimulated to a lesser extent by 25 mM of ammonium acetate, and markedly inhibited by sodium acetate (PubMed:18499658).SUBUNIT Associates with the CTF18-RFC complex (PubMed:18499658). Associates with a cohesin complex composed of RAD21, SMC1 proteins and SMC3 (PubMed:17105772). Interacts with CHTF18 (PubMed:18499658). Interacts with DSCC1 (PubMed:18499658). Interacts with FEN1; this interaction is direct and increases flap endonuclease activity of FEN1 (PubMed:18499658). Interacts with PCNA (PubMed:18499658). Interacts with POLR1A and UBTF (PubMed:26089203). Interacts with RAD21, SMC1 proteins and SMC3 (PubMed:17105772). Interacts with RFC2 (PubMed:18499658). Interacts with TIMELESS; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea (PubMed:20124417, PubMed:26503245).SUBUNIT (Microbial infection) Interacts with bovine papillomavirus type 1 regulatory protein E2; this interaction stimulates the recruitment of E2 onto mitotic chromosomes.TISSUE SPECIFICITY Expressed in melanoma cells. Not detected in epidermal melanocytes of normal skin (at protein level) (PubMed:23116066). Highly expressed in spleen, B-cells, thymus, testis, ovary, small intestine and pancreas (PubMed:9013641). Very low expression seen in brain (PubMed:9013641). Expressed in dividing cells and/or cells undergoing high levels of recombination (PubMed:9013641). No expression detected in cells signaled to terminally differentiate (PubMed:9013641). Expressed weakly in keratinocytes (PubMed:8798685).INDUCTION Up-regulated by serum (at protein level) (PubMed:26089203). Up-regulated by fibroblast growth factor FGF7 (PubMed:8798685). Expressed in keratinocyte growth factor-stimulated cells but not in EGF and IL1-beta-treated keratinocytes (PubMed:8798685). Up-regulated with progression from noninvasive to invasive melanoma (PubMed:23116066).SIMILARITY Belongs to the DEAD box helicase family. DEAH subfamily. DDX11/CHL1 sub-subfamily.UniProtQ96FC91EQUAL970EQUALReactome Database ID Release 75535492Database 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=535492ReactomeR-HSA-5354921Reactome 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-535492.1Reactome Database ID Release 751791116Database 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=1791116ReactomeR-HSA-17911163Reactome 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-1791116.3ACTIVATIONReactome Database ID Release 751791229Database 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=1791229ReactomeR-HSA-17912291Reactome 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-1791229.1LEFT-TO-RIGHTExpression of DNAJB11The DNAJB11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13DNAJB11 geneReactome DB_ID: 5642247ENSEMBL:ENSG00000090520 DNAJB11DNAJB11EDJERJ3HDJ9PSEC0121UNQ537/PRO1080ENSEMBLENSG00000090520Reactome Database ID Release 755642247Database 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=5642247ReactomeR-HSA-56422471Reactome 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-5642247.1HEDJDNAJB11ERdj3Reactome DB_ID: 381040UniProt:Q9UBS4 DNAJB11DNAJB11EDJERJ3HDJ9PSEC0121UNQ537/PRO1080FUNCTION As a co-chaperone for HSPA5 it is required for proper folding, trafficking or degradation of proteins (PubMed:10827079, PubMed:15525676, PubMed:29706351). Binds directly to both unfolded proteins that are substrates for ERAD and nascent unfolded peptide chains, but dissociates from the HSPA5-unfolded protein complex before folding is completed (PubMed:15525676). May help recruiting HSPA5 and other chaperones to the substrate. Stimulates HSPA5 ATPase activity (PubMed:10827079). It is necessary for maturation and correct trafficking of PKD1 (PubMed:29706351).SUBUNIT Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. Binds to denatured substrates in an ATP-independent manner. Interacts via the J domain with HSPA5 in an ATP-dependent manner.TISSUE SPECIFICITY Widely expressed.INDUCTION By endoplasmic reticulum stress-inducing agents such as thapsigargin and tunicamycin.PTM Contains high-mannose Endo H-sensitive carbohydrates.PTM Cys-169, Cys-171, Cys-193 and Cys-196 form intramolecular disulfide bonds. The preferential partner for each Cys is not known.PTM Thr-188 was reported to be phosphorylated upon DNA damage by ATM or ATR; however as this position has been shown to be in the ER lumen, the in vivo relevance is not proven.CAUTION PubMed:11584023 reported a cytosolic, as well as nuclear subcellular location. This result was obtained using an N-terminally GFP-tagged construct which most probably affected signal peptide-driven targeting to the ER. As a consequence, the in vivo revelance of the observed interaction with APOBEC1, a nuclear protein, is dubious. This holds true for the interaction with PWP1.UniProtQ9UBS423EQUAL358EQUALReactome Database ID Release 75381040Database 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=381040ReactomeR-HSA-3810401Reactome 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-381040.1Reactome Database ID Release 751791075Database 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=1791075ReactomeR-HSA-17910754Reactome 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-1791075.410827079Pubmed2000HEDJ, an Hsp40 co-chaperone localized to the endoplasmic reticulum of human cellsYu, MHaslam, RHHaslam, DBJ Biol Chem 275:24984-92ACTIVATIONReactome Database ID Release 751791206Database 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=1791206ReactomeR-HSA-17912061Reactome 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-1791206.1LEFT-TO-RIGHTExpression of DNAJB9The DNAJB9 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13DNAJB9 geneReactome DB_ID: 5642289ENSEMBL:ENSG00000128590 DNAJB9DNAJB9MDG1UNQ743/PRO1471ENSEMBLENSG00000128590Reactome Database ID Release 755642289Database 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=5642289ReactomeR-HSA-56422891Reactome 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-5642289.1MDG1DNAJB9ERdj4Reactome DB_ID: 381010UniProt:Q9UBS3 DNAJB9DNAJB9MDG1UNQ743/PRO1471FUNCTION Co-chaperone for Hsp70 protein HSPA5/BiP that acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (By similarity). J domain-containing co-chaperones stimulate the ATPase activity of Hsp70 proteins and are required for efficient substrate recognition by Hsp70 proteins (PubMed:18400946). In the unstressed endoplasmic reticulum, interacts with the luminal region of ERN1/IRE1 and selectively recruits HSPA5/BiP: HSPA5/BiP disrupts the dimerization of the active ERN1/IRE1 luminal region, thereby inactivating ERN1/IRE1 (By similarity). Also involved in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins. Required for survival of B-cell progenitors and normal antibody production (By similarity).SUBUNIT Interacts with HSPA5/BiP; interaction is direct (By similarity). Interacts with ERN1/IRE1 (via the luminal region) (By similarity). Interacts with DERL1 (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed at highest level in the liver, placenta and kidney (PubMed:11836248).DOMAIN The J domain stimulates the ATPase activity of HSPA5/BiP, while the divergent targeting domain is required for efficient substrate recognition by HSPA5/BiP. The divergent targeting domain specifically recognizes and binds to aggregation-prone sequences.UniProtQ9UBS31EQUAL223EQUALReactome Database ID Release 75381010Database 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=381010ReactomeR-HSA-3810101Reactome 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-381010.1Reactome Database ID Release 751791124Database 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=1791124ReactomeR-HSA-17911244Reactome 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-1791124.4ACTIVATIONReactome Database ID Release 751791214Database 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=1791214ReactomeR-HSA-17912141Reactome 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-1791214.1LEFT-TO-RIGHTExpression of EDEMThe EDEM gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13EDEM1 geneReactome DB_ID: 5642260ENSEMBL:ENSG00000134109 EDEM1EDEM1EDEMKIAA0212ENSEMBLENSG00000134109Reactome Database ID Release 755642260Database 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=5642260ReactomeR-HSA-56422601Reactome 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-5642260.1EDEMEDEM1Reactome DB_ID: 381083endoplasmic reticulum quality control compartmentGENE ONTOLOGYGO:0044322UniProt:Q92611 EDEM1EDEM1EDEMKIAA0212FUNCTION Extracts misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle. It is directly involved in endoplasmic reticulum-associated degradation (ERAD) and targets misfolded glycoproteins for degradation in an N-glycan-independent manner, probably by forming a complex with SEL1L. It has low mannosidase activity, catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2.SUBUNIT Interacts with DNAJC10 (By similarity). Interacts with DERL2 and DERL3. Binds to SEL1L.SIMILARITY Belongs to the glycosyl hydrolase 47 family.UniProtQ926111EQUAL657EQUALReactome Database ID Release 75381083Database 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=381083ReactomeR-HSA-3810832Reactome 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-381083.2Reactome Database ID Release 751791155Database 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=1791155ReactomeR-HSA-17911554Reactome 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-1791155.4ACTIVATIONReactome Database ID Release 751791197Database 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=1791197ReactomeR-HSA-17911971Reactome 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-1791197.1LEFT-TO-RIGHTExpression of EXTL1The EXTL1 gene is transcribed to yield mRNA and the mRNA is translated to yield exostosin-like 1 (EXTL1) protein (Wise et al. 1997, Saito et al. 1998).Authored: Jassal, Bijay, 2016-12-22Reviewed: D'Eustachio, Peter, 2017-01-06Edited: Jassal, Bijay, 2016-12-22EXTL1 geneReactome DB_ID: 8953370ENSEMBL:ENSG00000158008 EXTL1EXTL1EXTLENSEMBLENSG00000158008Reactome Database ID Release 758953370Database 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=8953370ReactomeR-HSA-89533701Reactome 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-8953370.1EXTL1Exostosin-like 1 ecNumber2.4.1.224/ecNumberEXTL1_HUMANReactome DB_ID: 8953369UniProt:Q92935 EXTL1EXTL1EXTLFUNCTION Probable glycosyltransferase.PATHWAY Protein modification; protein glycosylation.SIMILARITY Belongs to the glycosyltransferase 47 family.UniProtQ929351EQUAL676EQUALReactome Database ID Release 758953369Database 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=8953369ReactomeR-HSA-89533691Reactome 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-8953369.1Reactome Database ID Release 758953336Database 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=8953336ReactomeR-HSA-89533363Reactome 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-8953336.39037597Pubmed1997Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene familyWise, C AClines, G AMassa, HTrask, B JLovett, MGenome Res. 7:10-69473480Pubmed1998Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene familySaito, TSeki, NYamauchi, MTsuji, SHayashi, AKozuma, SHori, TBiochem. Biophys. Res. Commun. 243:61-6ACTIVATIONReactome Database ID Release 758954147Database 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=8954147ReactomeR-HSA-89541471Reactome 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-8954147.1LEFT-TO-RIGHTExpression of EXTL2The EXTL2 gene is transcribed to yield mRNA and the mRNA is translated to yield exostosin-like 2 (EXTL2) protein (Wuyts et al. 1997, Saito et al. 1998).Authored: Jassal, Bijay, 2016-12-22Reviewed: D'Eustachio, Peter, 2017-01-06Edited: Jassal, Bijay, 2016-12-22EXTL2 geneReactome DB_ID: 8953371ENSEMBL:ENSG00000162694 EXTL2EXTL2EXTR2ENSEMBLENSG00000162694Reactome Database ID Release 758953371Database 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=8953371ReactomeR-HSA-89533711Reactome 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-8953371.1EXTL2Exostosin-like 2 ecNumber2.4.1.223/ecNumberEXTL2_HUMANReactome DB_ID: 8953372UniProt:Q9UBQ6 EXTL2EXTL2EXTR2FUNCTION Glycosyltransferase required for the biosynthesis of heparan-sulfate and responsible for the alternating addition of beta-1-4-linked glucuronic acid (GlcA) and alpha-1-4-linked N-acetylglucosamine (GlcNAc) units to nascent heparan sulfate chains.PATHWAY Glycan metabolism; heparan sulfate biosynthesis.TISSUE SPECIFICITY Ubiquitous.PTM The soluble form derives from the membrane form by proteolytic processing.SIMILARITY Belongs to the glycosyltransferase 47 family.UniProtQ9UBQ61EQUAL330EQUALReactome Database ID Release 758953372Database 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=8953372ReactomeR-HSA-89533721Reactome 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-8953372.1Reactome Database ID Release 758953356Database 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=8953356ReactomeR-HSA-89533563Reactome 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-8953356.39450183Pubmed1997Identification and characterization of a novel member of the EXT gene family, EXTL2Wuyts, WVan Hul, WHendrickx, JSpeleman, FWauters, JDe Boulle, Kvan Roy, NVan Agtmael, TBossuyt, PWillems, P JEur. J. Hum. Genet. 5:382-9ACTIVATIONReactome Database ID Release 758954148Database 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=8954148ReactomeR-HSA-89541481Reactome 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-8954148.1LEFT-TO-RIGHTExpression of EXTL3The EXTL3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13EXTL3 geneReactome DB_ID: 5642277ENSEMBL:ENSG00000012232 EXTL3EXTL3EXTL1LEXTR1KIAA0519ENSEMBLENSG00000012232Reactome Database ID Release 755642277Database 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=5642277ReactomeR-HSA-56422771Reactome 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-5642277.1EXTL3Exostosin-like 3EXTL3_HUMANReactome DB_ID: 535476UniProt:O43909 EXTL3EXTL3EXTL1LEXTR1KIAA0519FUNCTION Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs) (PubMed:28132690, PubMed:28148688). Required for the function of REG3A in regulating keratinocyte proliferation and differentiation (PubMed:22727489).PATHWAY Glycan metabolism; heparan sulfate biosynthesis.SUBUNIT Interacts with REG3A.TISSUE SPECIFICITY Ubiquitous. Expressed in keratinocytes.SIMILARITY Belongs to the glycosyltransferase 47 family.CAUTION It is uncertain whether Met-1, Met-6 or Met-20 is the initiator.UniProtO439091EQUAL919EQUALReactome Database ID Release 75535476Database 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=535476ReactomeR-HSA-5354761Reactome 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-535476.1Reactome Database ID Release 751791144Database 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=1791144ReactomeR-HSA-17911444Reactome 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-1791144.4ACTIVATIONReactome Database ID Release 751791240Database 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=1791240ReactomeR-HSA-17912401Reactome 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-1791240.1LEFT-TO-RIGHTExpression of FKBP14The FKBP14 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13FKBP14 geneReactome DB_ID: 5642302ENSEMBL:ENSG00000106080 FKBP14 geneFKBP14 geneFKBP14FKBP22UNQ322/PRO381ENSEMBLENSG00000106080Reactome Database ID Release 755642302Database 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=5642302ReactomeR-HSA-56423021Reactome 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-5642302.1FKBP14FK506-binding protein 14FKB14_HUMANReactome DB_ID: 535607UniProt:Q9NWM8 FKBP14FKBP14FKBP22UNQ322/PRO381FUNCTION PPIase which accelerates the folding of proteins during protein synthesis. Has a preference for substrates containing 4-hydroxylproline modifications, including type III collagen. May also target type VI and type X collagens.ACTIVITY REGULATION Inhibited by tacrolimus/FK506.SUBUNIT Monomer (PubMed:24821723, PubMed:24272907). Homodimer (PubMed:24821723, PubMed:24272907). Interacts with type III, type IV and type X collagens (PubMed:24821723).UniProtQ9NWM820EQUAL211EQUALReactome Database ID Release 75535607Database 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=535607ReactomeR-HSA-5356071Reactome 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-535607.1Reactome Database ID Release 751791114Database 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=1791114ReactomeR-HSA-17911144Reactome 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-1791114.4ACTIVATIONReactome Database ID Release 751791201Database 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=1791201ReactomeR-HSA-17912011Reactome 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-1791201.1LEFT-TO-RIGHTExpression of ARFGAP1 (GAP)The GAP gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13ARFGAP1 geneReactome DB_ID: 5642287ENSEMBL:ENSG00000101199 ARFGAP1ARFGAP1ARF1GAPENSEMBLENSG00000101199Reactome Database ID Release 755642287Database 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=5642287ReactomeR-HSA-56422871Reactome 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-5642287.1GAPARFGAP1Reactome DB_ID: 200464UniProt:Q8N6T3 ARFGAP1ARFGAP1ARF1GAPFUNCTION GTPase-activating protein (GAP) for the ADP ribosylation factor 1 (ARF1). Involved in membrane trafficking and /or vesicle transport. Promotes hydrolysis of the ARF1-bound GTP and thus, is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles, a prerequisite for vesicle's fusion with target compartment. Probably regulates ARF1-mediated transport via its interaction with the KDELR proteins and TMED2. Overexpression induces the redistribution of the entire Golgi complex to the endoplasmic reticulum, as when ARF1 is deactivated. Its activity is stimulated by phosphoinosides and inhibited by phosphatidylcholine (By similarity).SUBUNIT Interacts with ARF1. Interacts with the COPI coat proteins, KDELR1 and TMED2. The interaction with TMED2 inhibits the GAP activity (By similarity).DOMAIN The region downstream of Arf-GAP domain is essential to GAP activity in vivo. This region may be required for its targeting to Golgi membranes (By similarity).UniProtQ8N6T31EQUAL406EQUALReactome Database ID Release 75200464Database 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=200464ReactomeR-HSA-2004641Reactome 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-200464.1Reactome Database ID Release 751791064Database 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=1791064ReactomeR-HSA-17910644Reactome 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-1791064.4ACTIVATIONReactome Database ID Release 751791196Database 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=1791196ReactomeR-HSA-17911961Reactome 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-1791196.1LEFT-TO-RIGHTExpression of GFPT1The GFPT1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13GFPT1 geneReactome DB_ID: 5642312ENSEMBL:ENSG00000198380 GFPT1GFPT1GFATGFPTENSEMBLENSG00000198380Reactome Database ID Release 755642312Database 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=5642312ReactomeR-HSA-56423121Reactome 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-5642312.1GFPT1Glucosamine--fructose-6-phosphate aminotransferase (isomerizing) 1Reactome DB_ID: 532216UniProt:Q06210 GFPT1GFPT1GFATGFPTFUNCTION Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Regulates the circadian expression of clock genes ARNTL/BMAL1 and CRY1.PATHWAY Nucleotide-sugar biosynthesis; UDP-N-acetyl-alpha-D-glucosamine biosynthesis; alpha-D-glucosamine 6-phosphate from D-fructose 6-phosphate: step 1/1.SUBUNIT Homotetramer (Probable), may also exist as homodimers.TISSUE SPECIFICITY Isoform 1 is predominantly expressed in skeletal muscle. Not expressed in brain. Seems to be selectively expressed in striated muscle.UniProtQ062102EQUAL699EQUALReactome Database ID Release 75532216Database 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=532216ReactomeR-HSA-5322161Reactome 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-532216.1Reactome Database ID Release 751791088Database 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=1791088ReactomeR-HSA-17910884Reactome 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-1791088.4ACTIVATIONReactome Database ID Release 751791213Database 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=1791213ReactomeR-HSA-17912131Reactome 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-1791213.1LEFT-TO-RIGHTExpression of GOSR2The GOSR2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13GOSR2 geneReactome DB_ID: 5642202ENSEMBL:ENSG00000108433 GOSR2GOSR2GS27ENSEMBLENSG00000108433Reactome Database ID Release 755642202Database 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=5642202ReactomeR-HSA-56422021Reactome 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-5642202.1GOSR2Golgi SNAP receptor complex member 2GOSR2_HUMANReactome DB_ID: 535472endoplasmic reticulum-Golgi intermediate compartment membraneGENE ONTOLOGYGO:0033116UniProt:O14653 GOSR2GOSR2GS27FUNCTION Involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network.SUBUNIT Part of a unique SNARE complex composed of the Golgi SNAREs GOSR1, STX5 and YKT6 (By similarity). Interacts (via IxM motif) with SEC24C and SEC24D; mediates GOSR2 packaging into COPII-coated vesicles (PubMed:18843296).SIMILARITY Belongs to the GOSR2 family.UniProtO146531EQUAL212EQUALReactome Database ID Release 75535472Database 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=535472ReactomeR-HSA-5354722Reactome 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-535472.2Reactome Database ID Release 751791154Database 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=1791154ReactomeR-HSA-17911544Reactome 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-1791154.4ACTIVATIONReactome Database ID Release 751791231Database 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=1791231ReactomeR-HSA-17912311Reactome 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-1791231.1LEFT-TO-RIGHTExpression of GSK3AThe GSK3A gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13GSK3A geneReactome DB_ID: 5642288ENSEMBL:ENSG00000105723 GSK3AGSK3AENSEMBLENSG00000105723Reactome Database ID Release 755642288Database 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=5642288ReactomeR-HSA-56422881Reactome 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-5642288.1GSK3AGlycogen synthase kinase-3 alphaKG3A_HUMANReactome DB_ID: 198326UniProt:P49840 GSK3AGSK3AFUNCTION Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350). Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). Regulates glycogen metabolism in liver, but not in muscle (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001). In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088). Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548). May be involved in the regulation of replication in pancreatic beta-cells (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity).ACTIVITY REGULATION Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.SUBUNIT Monomer. Interacts with ARRB2 (By similarity). Interacts with AXIN1 and CTNNB1/beta-catenin (PubMed:17229088). Interacts with CTNND2 (PubMed:19706605). Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X (PubMed:18846110). Interacts with TNFRSF10B (PubMed:18846110).SUBUNIT (Microbial infection) Interacts with M.tuberculosis PtpA.PTM Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279.PTM (Microbial infection) Dephosphorylated at Tyr-279 by M.tuberculosis PtpA, which leads to prevention of apoptosis during early stages of microbial infection.MISCELLANEOUS Higher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.UniProtP498402EQUAL483EQUALReactome Database ID Release 75198326Database 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=198326ReactomeR-HSA-1983261Reactome 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-198326.1Reactome Database ID Release 751791054Database 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=1791054ReactomeR-HSA-17910544Reactome 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-1791054.4ACTIVATIONReactome Database ID Release 751791210Database 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=1791210ReactomeR-HSA-17912101Reactome 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-1791210.1LEFT-TO-RIGHTExpression of HDGFThe HDGF gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13HDGF geneReactome DB_ID: 5642236ENSEMBL:ENSG00000143321 HDGFHDGFHMG1L2ENSEMBLENSG00000143321Reactome Database ID Release 755642236Database 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=5642236ReactomeR-HSA-56422361Reactome 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-5642236.1HDGFHepatoma-derived growth factorHDGF_HUMANReactome DB_ID: 535593UniProt:P51858 HDGFHDGFHMG1L2SUBUNIT Monomer, and domain-swapped homodimer (PubMed:17270212).TISSUE SPECIFICITY Ubiquitous.DOMAIN The PWWP domain harbors the heparin-binding sites and is responsible for DNA-binding, while the C-terminal region is essentially unstructured.DOMAIN The N-terminal region does not contain a typical signal sequence but is required for secretion (By similarity). It also determines exosomal location (PubMed:26845719).PTM Sumoylated with SUMO1. Sumoylation prevents binding to chromatin.PTM Phosphorylation at Ser-165 is likely to be required for secretion.SIMILARITY Belongs to the HDGF family.UniProtP518581EQUAL240EQUALReactome Database ID Release 75535593Database 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=535593ReactomeR-HSA-5355931Reactome 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-535593.1Reactome Database ID Release 751791112Database 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=1791112ReactomeR-HSA-17911123Reactome 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-1791112.3ACTIVATIONReactome Database ID Release 751791207Database 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=1791207ReactomeR-HSA-17912071Reactome 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-1791207.1LEFT-TO-RIGHTExpression of HYOU1The HYOU1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13HYOU1 geneReactome DB_ID: 5642278ENSEMBL:ENSG00000149428 HYOU1HYOU1GRP170ORP150ENSEMBLENSG00000149428Reactome Database ID Release 755642278Database 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=5642278ReactomeR-HSA-56422781Reactome 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-5642278.1HYOU1Hypoxia up-regulated protein 1HYOU1_HUMANReactome DB_ID: 535542UniProt:Q9Y4L1 HYOU1HYOU1GRP170ORP150FUNCTION Has a pivotal role in cytoprotective cellular mechanisms triggered by oxygen deprivation. May play a role as a molecular chaperone and participate in protein folding.SUBUNIT Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX.TISSUE SPECIFICITY Highly expressed in tissues that contain well-developed endoplasmic reticulum and synthesize large amounts of secretory proteins. Highly expressed in liver and pancreas and lower expression in brain and kidney. Also expressed in macrophages within aortic atherosclerotic plaques, and in breast cancers.INDUCTION By hypoxia and also by 2-deoxyglucose or tunicamycin.SIMILARITY Belongs to the heat shock protein 70 family.UniProtQ9Y4L133EQUAL999EQUALReactome Database ID Release 75535542Database 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=535542ReactomeR-HSA-5355421Reactome 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-535542.1Reactome Database ID Release 751791066Database 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=1791066ReactomeR-HSA-17910664Reactome 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-1791066.4ACTIVATIONReactome Database ID Release 751791255Database 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=1791255ReactomeR-HSA-17912551Reactome 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-1791255.1LEFT-TO-RIGHTExpression of KDELR3The KDELR3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13KDELR3 geneReactome DB_ID: 5642222ENSEMBL:ENSG00000100196 KDELR3KDELR3ENSEMBLENSG00000100196Reactome Database ID Release 755642222Database 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=5642222ReactomeR-HSA-56422221Reactome 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-5642222.1KDELR3ER lumen protein retaining receptor 3ERD23_HUMANReactome DB_ID: 535518UniProt:O43731 KDELR3KDELR3FUNCTION Receptor for the C-terminal sequence motif K-D-E-L that is present on endoplasmic reticulum resident proteins and that mediates their recycling from the Golgi back to the endoplasmic reticulum.DOMAIN Binds the C-terminal sequence motif K-D-E-L in a hydrophilic cavity between the transmembrane domains. This triggers a conformation change that exposes a Lys-rich patch on the cytosolic surface of the protein (By similarity). This patch mediates recycling from the Golgi to the endoplasmic reticulum, probably via COPI vesicles (By similarity).SIMILARITY Belongs to the ERD2 family.UniProtO437311EQUAL214EQUALReactome Database ID Release 75535518Database 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=535518ReactomeR-HSA-5355181Reactome 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-535518.1Reactome Database ID Release 751791123Database 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=1791123ReactomeR-HSA-17911234Reactome 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-1791123.4ACTIVATIONReactome Database ID Release 751791202Database 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=1791202ReactomeR-HSA-17912021Reactome 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-1791202.1LEFT-TO-RIGHTExpression of KLHDC3The KLHDC3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13KLHDC3 geneReactome DB_ID: 5642295ENSEMBL:ENSG00000124702 KLHDC3KLHDC3PEASENSEMBLENSG00000124702Reactome Database ID Release 755642295Database 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=5642295ReactomeR-HSA-56422951Reactome 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-5642295.1KLHDC3Kelch domain-containing protein 3KLDC3_HUMANReactome DB_ID: 535552UniProt:Q9BQ90 KLHDC3KLHDC3PEASFUNCTION May be involved in meiotic recombination process.UniProtQ9BQ901EQUAL382EQUALReactome Database ID Release 75535552Database 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=535552ReactomeR-HSA-5355521Reactome 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-535552.1Reactome Database ID Release 751791177Database 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=1791177ReactomeR-HSA-17911774Reactome 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-1791177.4ACTIVATIONReactome Database ID Release 751791216Database 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=1791216ReactomeR-HSA-17912161Reactome 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-1791216.1LEFT-TO-RIGHTExpression of LMNAThe LMNA gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13LMNA geneReactome DB_ID: 5642300ENSEMBL:ENSG00000160789 LMNALMNALMN1ENSEMBLENSG00000160789Reactome Database ID Release 755642300Database 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=5642300ReactomeR-HSA-56423001Reactome 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-5642300.1LMNALMNA(1-664)Lamin-A/CLMNA_HUMANReactome DB_ID: 535479UniProt:P02545 LMNALMNALMN1FUNCTION Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin. Lamin A and C are present in equal amounts in the lamina of mammals. Plays an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation (PubMed:10080180, PubMed:22431096, PubMed:10814726, PubMed:11799477, PubMed:18551513). Required for osteoblastogenesis and bone formation (PubMed:12075506, PubMed:15317753, PubMed:18611980). Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone (PubMed:10587585). Required for cardiac homeostasis (PubMed:10580070, PubMed:12927431, PubMed:18611980, PubMed:23666920).FUNCTION Prelamin-A/C can accelerate smooth muscle cell senescence. It acts to disrupt mitosis and induce DNA damage in vascular smooth muscle cells (VSMCs), leading to mitotic failure, genomic instability, and premature senescence.SUBUNIT Homodimer of lamin A and lamin C. Interacts with lamin-associated polypeptides IA, IB and TMPO-alpha, RB1 and with emerin. Interacts with SREBF1, SREBF2, SUN2 and TMEM43. Interacts with TMEM201 (By similarity). Proteolytically processed isoform A interacts with NARF. Interacts with SUN1. Prelamin-A/C interacts with EMD. Interacts with MLIP. Interacts with DMPK; may regulate nuclear envelope stability. Interacts with SUV39H1; the interaction increases stability of SUV39H1. Interacts with SYNE2. Interacts with ITSN1 isoform 2 (PubMed:29599122).TISSUE SPECIFICITY In the arteries, prelamin-A/C accumulation is not observed in young healthy vessels but is prevalent in medial vascular smooth muscle cells (VSMCs) from aged individuals and in atherosclerotic lesions, where it often colocalizes with senescent and degenerate VSMCs. Prelamin-A/C expression increases with age and disease. In normal aging, the accumulation of prelamin-A/C is caused in part by the down-regulation of ZMPSTE24/FACE1 in response to oxidative stress.PTM Increased phosphorylation of the lamins occurs before envelope disintegration and probably plays a role in regulating lamin associations.PTM Proteolytic cleavage of the C-terminal of 18 residues of prelamin-A/C results in the production of lamin-A/C. The prelamin-A/C maturation pathway includes farnesylation of CAAX motif, ZMPSTE24/FACE1 mediated cleavage of the last three amino acids, methylation of the C-terminal cysteine and endoproteolytic removal of the last 15 C-terminal amino acids. Proteolytic cleavage requires prior farnesylation and methylation, and absence of these blocks cleavage.PTM Sumoylation is necessary for the localization to the nuclear envelope.PTM Farnesylation of prelamin-A/C facilitates nuclear envelope targeting.DISEASE Defects in LMNA may cause a late-onset cardiocutaneous progeria syndrome characterized by cutaneous manifestations of aging appearing in the third decade of life, cardiac valve calcification and dysfunction, prominent atherosclerosis, and cardiomyopathy, leading to death on average in the fourth decade.MISCELLANEOUS There are three types of lamins in human cells: A, B, and C.MISCELLANEOUS The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively.SIMILARITY Belongs to the intermediate filament family.UniProtP025451EQUAL664EQUALReactome Database ID Release 75535479Database 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=535479ReactomeR-HSA-5354791Reactome 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-535479.1Reactome Database ID Release 751791128Database 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=1791128ReactomeR-HSA-17911283Reactome 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-1791128.3ACTIVATIONReactome Database ID Release 751791218Database 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=1791218ReactomeR-HSA-17912181Reactome 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-1791218.1LEFT-TO-RIGHTExpression of PDIA5The PDIA5 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13PDIA5 geneReactome DB_ID: 5642244ENSEMBL:ENSG00000065485 PDIA5PDIA5PDIRENSEMBLENSG00000065485Reactome Database ID Release 755642244Database 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=5642244ReactomeR-HSA-56422441Reactome 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-5642244.1PDIA5Protein disulfide-isomerase A5PDIA5_HUMANReactome DB_ID: 535514UniProt:Q14554 PDIA5PDIA5PDIRSUBUNIT Interacts with CALR (via P-domain).SIMILARITY Belongs to the protein disulfide isomerase family.UniProtQ1455422EQUAL519EQUALReactome Database ID Release 75535514Database 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=535514ReactomeR-HSA-5355141Reactome 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-535514.1Reactome Database ID Release 751791122Database 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=1791122ReactomeR-HSA-17911224Reactome 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-1791122.4ACTIVATIONReactome Database ID Release 751791225Database 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=1791225ReactomeR-HSA-17912251Reactome 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-1791225.1LEFT-TO-RIGHTExpression of PDIA6 (Protein disulfide-isomerase A6)The PDIA6 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13PDIA6 geneReactome DB_ID: 5642213ENSEMBL:ENSG00000143870 PDIA6PDIA6ERP5P5TXNDC7ENSEMBLENSG00000143870Reactome Database ID Release 755642213Database 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=5642213ReactomeR-HSA-56422131Reactome 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-5642213.1PDIA6Protein disulfide-isomerase A6PDIA6_HUMANReactome DB_ID: 535530UniProt:Q15084 PDIA6PDIA6ERP5P5TXNDC7FUNCTION May function as a chaperone that inhibits aggregation of misfolded proteins (PubMed:12204115). Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling (PubMed:24508390). May also regulate the UPR via the EIF2AK3 UPR sensor (PubMed:24508390). Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin (PubMed:15466936).SUBUNIT Part of a large chaperone multiprotein complex comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (PubMed:12475965). Interacts with MICA on the surface of tumor cells, leading to MICA disulfide bond reduction which is required for its release from tumor cells (PubMed:17495932). Interacts with ITGB3 following platelet stimulation (PubMed:15466936). Interacts with ERN1; the interaction is direct (PubMed:24508390). Interacts with EIF2AK3 (PubMed:24508390).TISSUE SPECIFICITY Expressed in platelets (at protein level).SIMILARITY Belongs to the protein disulfide isomerase family.UniProtQ1508420EQUAL440EQUALReactome Database ID Release 75535530Database 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=535530ReactomeR-HSA-5355301Reactome 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-535530.1Reactome Database ID Release 751791131Database 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=1791131ReactomeR-HSA-17911314Reactome 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-1791131.412204115Pubmed2002Functional analysis of human P5, a protein disulfide isomerase homologueKikuchi, MDoi, ETsujimoto, IHoribe, TTsujimoto, YoshihideJ Biochem 132:451-515466936Pubmed2005A role for the thiol isomerase protein ERP5 in platelet functionJordan, PAStevens, JMHubbard, GPBarrett, NESage, TAuthi, KSGibbins, JMBlood 105:1500-77590364Pubmed1995Cloning and sequencing of the cDNA encoding human P5Hayano, TKikuchi, MGene 164:377-8ACTIVATIONReactome Database ID Release 751791223Database 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=1791223ReactomeR-HSA-17912231Reactome 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-1791223.1LEFT-TO-RIGHTExpression of PLA2G4BThe PLA2GB4B gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13PLA2G4B geneReactome DB_ID: 5642267ENSEMBL:ENSG00000243708 PLA2G4BPLA2G4BENSEMBLENSG00000243708Reactome Database ID Release 755642267Database 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=5642267ReactomeR-HSA-56422671Reactome 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-5642267.1PLA2G4BCytosolic phospholipase A2 betaPA24B_HUMANReactome DB_ID: 535541UniProt:P0C869 PLA2G4BPLA2G4BFUNCTION Calcium-dependent phospholipase A2 that selectively hydrolyzes glycerophospholipids in the sn-2 position with a preference for arachidonoyl phospholipids. Has a much weaker activity than PLA2G4A. Isoform 3 has calcium-dependent activity against palmitoyl-arachidonyl-phosphatidylethanolamine and low level lysophospholipase activity but no activity against phosphatidylcholine. Isoform 5 does have activity against phosphatidylcholine.ACTIVITY REGULATION Stimulated by cytosolic Ca(2+).TISSUE SPECIFICITY Widely expressed. Expressed at higher level in brain, heart, liver, cerebellum and pancreas. Isoform 3 is widely expressed.DOMAIN The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic Ca(2+) (By similarity).CAUTION Most tissues also express read-through transcripts from this gene into the upstream gene (JMJD7), some of which may encode fusion proteins.UniProtP0C8691EQUAL781EQUALReactome Database ID Release 75535541Database 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=535541ReactomeR-HSA-5355411Reactome 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-535541.1Reactome Database ID Release 751791071Database 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=1791071ReactomeR-HSA-17910714Reactome 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-1791071.4ACTIVATIONReactome Database ID Release 751791244Database 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=1791244ReactomeR-HSA-17912441Reactome 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-1791244.1LEFT-TO-RIGHTExpression of PPP2R5BThe PPP2R5B gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13PPP2R5B geneReactome DB_ID: 5642207ENSEMBL:ENSG00000068971 PPP2R5BPPP2R5BENSEMBLENSG00000068971Reactome Database ID Release 755642207Database 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=5642207ReactomeR-HSA-56422071Reactome 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-5642207.1PPP2R5BSerine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform2A5B_HUMANReactome DB_ID: 535469UniProt:Q15173 PPP2R5BPPP2R5BFUNCTION As the regulatory component of the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme, modulates substrate specificity, subcellular localization, and responsiveness to phosphorylation. The phosphorylated form mediates the interaction between PP2A and AKT1, leading to AKT1 dephosphorylation.SUBUNIT Component of the serine/threonine-protein phosphatase 2A complex (PP2A). This complex consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant scaffold subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:23135275). Interacts with SGO1 (PubMed:16541025). Interacts with AKT1 (PubMed:21329884). Interacts with CUL3 and KLHL15; this interaction leads to proteasomal degradation (PubMed:23135275).TISSUE SPECIFICITY Highest expression in brain.INDUCTION By retinoic acid; in neuroblastoma cell lines.PTM Ubiquitinated by E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation.SIMILARITY Belongs to the phosphatase 2A regulatory subunit B56 family.UniProtQ151731EQUAL497EQUALReactome Database ID Release 75535469Database 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=535469ReactomeR-HSA-5354691Reactome 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-535469.1Reactome Database ID Release 751791096Database 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=1791096ReactomeR-HSA-17910964Reactome 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-1791096.4ACTIVATIONReactome Database ID Release 751791193Database 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=1791193ReactomeR-HSA-17911931Reactome 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-1791193.1LEFT-TO-RIGHTExpression of SERP1 (RAMP4)The RAMP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SERP1 geneReactome DB_ID: 5642299ENSEMBL:ENSG00000120742 SERP1SERP1RAMP4ENSEMBLENSG00000120742Reactome Database ID Release 755642299Database 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=5642299ReactomeR-HSA-56422991Reactome 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-5642299.1SERP1RAMP4Reactome DB_ID: 381045UniProt:Q9Y6X1 SERP1SERP1RAMP4FUNCTION Interacts with target proteins during their translocation into the lumen of the endoplasmic reticulum. Protects unfolded target proteins against degradation during ER stress. May facilitate glycosylation of target proteins after termination of ER stress. May modulate the use of N-glycosylation sites on target proteins (By similarity).SUBUNIT Interacts with SEC61B, SEC61A1 and the SEC61 complex. Interacts with CANX (By similarity).SIMILARITY Belongs to the RAMP4 family.UniProtQ9Y6X11EQUAL66EQUALReactome Database ID Release 75381045Database 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=381045ReactomeR-HSA-3810451Reactome 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-381045.1Reactome Database ID Release 751791167Database 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=1791167ReactomeR-HSA-17911674Reactome 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-1791167.421282569Pubmed2011Role of miR-204 in the regulation of apoptosis, endoplasmic reticulum stress response, and inflammation in human trabecular meshwork cellsLi, GLuna, CQiu, JEpstein, DLGonzalez, PInvest Ophthalmol Vis Sci 52:2999-300710601334Pubmed1999Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylationYamaguchi, AHori, OStern, DMHartmann, EOgawa, STohyama, MJ Cell Biol 147:1195-204ACTIVATIONReactome Database ID Release 751791190Database 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=1791190ReactomeR-HSA-17911901Reactome 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-1791190.1LEFT-TO-RIGHTExpression of SHC1The SHC1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SHC1 geneReactome DB_ID: 5642218ENSEMBL:ENSG00000160691 SHC1SHC1SHCSHCAENSEMBLENSG00000160691Reactome Database ID Release 755642218Database 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=5642218ReactomeR-HSA-56422181Reactome 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-5642218.1SHCSHC1SHC1 p66SHC transforming proteinReactome DB_ID: 74680UniProt:P29353 SHC1SHC1SHCSHCAFUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc and isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p46Shc and isoform p52Shc may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span (By similarity). Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (PubMed:20010870). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2. Interacts with the N-terminal region of APS. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with PTK2/FAK1. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1188') (PubMed:23846654). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46.TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p46Shc and isoform p52Shc bind to phosphorylated Trk receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform p46Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation (By similarity).PTM Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to FLT4 and KIT signaling. Isoform p46Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light (By similarity). Tyrosine phosphorylated in response to FLT3 signaling (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Tyrosine phosphorylated by ligand-activated ALK. Tyrosine phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated by TEK/TIE2. May be tyrosine phosphorylated by activated PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma biopsy, where PTK2/FAK1 kinase activity is high, but not in normal brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may regulate interaction with GRB2.UniProtP293531EQUAL583EQUALReactome Database ID Release 7574680Database 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=74680ReactomeR-HSA-746801Reactome 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-74680.1Reactome Database ID Release 751791134Database 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=1791134ReactomeR-HSA-17911344Reactome 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-1791134.4ACTIVATIONReactome Database ID Release 751791246Database 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=1791246ReactomeR-HSA-17912461Reactome 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-1791246.1LEFT-TO-RIGHTExpression of SRPR (SRP Receptor subunit alpha)The SRPR gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SRPR geneReactome DB_ID: 5642266ENSEMBL:ENSG00000182934 SRPRSRPRSRPRAENSEMBLENSG00000182934Reactome Database ID Release 755642266Database 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=5642266ReactomeR-HSA-56422661Reactome 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-5642266.1SRPRSRP Receptor subunit alphaReactome DB_ID: 264970UniProt:P08240 SRPRASRPRASRPRFUNCTION Component of the SRP (signal recognition particle) receptor. Ensures, in conjunction with the signal recognition particle, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system.SUBUNIT Heterodimer with SRPRB.SUBUNIT (Microbial infection) May interact with Zika virus strain Mr-766 non-structural protein 4A/NS4A (PubMed:30550790). May interact with Zika virus French Polynesia 10087PF/2013 non-structural protein 4A/NS4A (PubMed:30550790).SUBUNIT (Microbial infection) May interact with Dengue virus DENV2 16681 non-structural protein 4A/NS4A.SIMILARITY Belongs to the GTP-binding SRP family.UniProtP082401EQUAL638EQUALReactome Database ID Release 75264970Database 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=264970ReactomeR-HSA-2649701Reactome 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-264970.1Reactome Database ID Release 751791139Database 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=1791139ReactomeR-HSA-17911394Reactome 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-1791139.4ACTIVATIONReactome Database ID Release 751791198Database 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=1791198ReactomeR-HSA-17911981Reactome 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-1791198.1LEFT-TO-RIGHTExpression of SRPRB (SRP Receptor subunit beta)The SRPRB gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SRPRB geneReactome DB_ID: 5642306ENSEMBL:ENSG00000144867 SRPRBSRPRBPSEC0230ENSEMBLENSG00000144867Reactome Database ID Release 755642306Database 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=5642306ReactomeR-HSA-56423061Reactome 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-5642306.1SRPRBSRP Receptor subunit betaReactome DB_ID: 265002UniProt:Q9Y5M8 SRPRBSRPRBPSEC0230FUNCTION Component of the SRP (signal recognition particle) receptor. Ensures, in conjunction with the signal recognition particle, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system. Has GTPase activity. May mediate the membrane association of SRPR (By similarity).SUBUNIT Heterodimer with SRPRA.SIMILARITY Belongs to the SRP receptor beta subunit family.UniProtQ9Y5M81EQUAL271EQUALReactome Database ID Release 75265002Database 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=265002ReactomeR-HSA-2650021Reactome 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-265002.1Reactome Database ID Release 751791060Database 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=1791060ReactomeR-HSA-17910604Reactome 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-1791060.4ACTIVATIONReactome Database ID Release 751791232Database 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=1791232ReactomeR-HSA-17912321Reactome 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-1791232.1LEFT-TO-RIGHTExpression of SSR1 (Trap alpha)The SSR1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SSR1 geneReactome DB_ID: 5642230ENSEMBL:ENSG00000124783 SSR1SSR1TRAPAPSEC0262ENSEMBLENSG00000124783Reactome Database ID Release 755642230Database 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=5642230ReactomeR-HSA-56422301Reactome 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-5642230.1SSR1Trap alphaTranslocon-associated protein subunit alphaSSRA_HUMANReactome DB_ID: 444588UniProt:P43307 SSR1SSR1TRAPAPSEC0262FUNCTION TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins. May be involved in the recycling of the translocation apparatus after completion of the translocation process or may function as a membrane-bound chaperone facilitating folding of translocated proteins.SUBUNIT Heterotetramer of TRAP-alpha, TRAP-beta, TRAP-delta and TRAP-gamma. Interacts with palmitoylated calnexin (CALX), the interaction is required for efficient folding of glycosylated proteins.DOMAIN Shows a remarkable charge distribution with the N-terminus being highly negatively charged, and the cytoplasmic C-terminus positively charged.MISCELLANEOUS Seems to bind calcium.SIMILARITY Belongs to the TRAP-alpha family.UniProtP4330719EQUAL286EQUALReactome Database ID Release 75444588Database 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=444588ReactomeR-HSA-4445881Reactome 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-444588.1Reactome Database ID Release 751791164Database 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=1791164ReactomeR-HSA-17911644Reactome 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-1791164.4ACTIVATIONReactome Database ID Release 751791224Database 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=1791224ReactomeR-HSA-17912241Reactome 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-1791224.1LEFT-TO-RIGHTExpression of SULT1A3The SULT1A3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SULT1A3 geneReactome DB_ID: 5642296ENSEMBL:ENSG00000261052 SULT1A3SULT1A3STMENSEMBLENSG00000261052Reactome Database ID Release 755642296Database 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=5642296ReactomeR-HSA-56422961Reactome 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-5642296.1SULT1A3ST1A3_HUMANReactome DB_ID: 5634741UniProt:P0DMM9 SULT1A3SULT1A3STMFUNCTION Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of phenolic monoamines (neurotransmitters such as dopamine, norepinephrine and serotonin) and phenolic and catechol drugs.SUBUNIT Homodimer.TISSUE SPECIFICITY Liver, colon, kidney, lung, brain, spleen, small intestine, placenta and leukocyte.PTM The N-terminus is blocked.SIMILARITY Belongs to the sulfotransferase 1 family.CAUTION Found in a segmental duplication on p arm of chromosome 16 giving rise to two identical copies of this gene sharing exons with SLX1A and SLX1B. The ORFs of SULT1A3 and SULT1A4 differ with only a single nucleotide change that does not alter the encoded amino acid. It is not possible to determine whether any individual polymorphism is present within SULT1A3 or SULT1A4 (PubMed:15358107).UniProtP0DMM91EQUAL295EQUALReactome Database ID Release 755634741Database 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=5634741ReactomeR-HSA-56347411Reactome 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-5634741.1Reactome Database ID Release 751791108Database 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=1791108ReactomeR-HSA-17911084Reactome 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-1791108.4ACTIVATIONReactome Database ID Release 751791194Database 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=1791194ReactomeR-HSA-17911941Reactome 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-1791194.1LEFT-TO-RIGHTExpression of SYVN1 (HRD1)The SYVN1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SYVN1 geneReactome DB_ID: 5642262ENSEMBL:ENSG00000162298 SYVN1SYVN1HRD1KIAA1810ENSEMBLENSG00000162298Reactome Database ID Release 755642262Database 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=5642262ReactomeR-HSA-56422621Reactome 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-5642262.1SYVN1SYVN1(1-617)E3 ubiquitin-protein ligase synoviolinSYVN1_HUMANReactome DB_ID: 535496UniProt:Q86TM6 SYVN1SYVN1HRD1KIAA1810FUNCTION E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation (PubMed:12459480, PubMed:12646171, PubMed:12975321, PubMed:14593114, PubMed:16289116, PubMed:16847254, PubMed:17059562, PubMed:17141218, PubMed:17170702, PubMed:22607976, PubMed:26471130, PubMed:28827405). Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:12459480, PubMed:12646171, PubMed:12975321, PubMed:14593114, PubMed:16289116, PubMed:16847254, PubMed:17059562, PubMed:17141218, PubMed:17170702, PubMed:22607976, PubMed:26471130, PubMed:28842558). Also promotes the degradation of normal but naturally short-lived proteins such as SGK. Protects cells from ER stress-induced apoptosis. Protects neurons from apoptosis induced by polyglutamine-expanded huntingtin (HTT) or unfolded GPR37 by promoting their degradation (PubMed:17141218). Sequesters p53/TP53 in the cytoplasm and promotes its degradation, thereby negatively regulating its biological function in transcription, cell cycle regulation and apoptosis (PubMed:17170702). Mediates the ubiquitination and subsequent degradation of cytoplasmic NFE2L1 (By similarity). During the early stage of B cell development, required for degradation of the pre-B cell receptor (pre-BCR) complex, hence supporting further differentiation into mature B cells (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer (PubMed:16289116). Interacts with p53/TP53 (PubMed:17170702). Interacts with HTT (PubMed:17141218). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1 (PubMed:16289116, PubMed:16186509, PubMed:18264092, PubMed:26471130, PubMed:28827405). FAM8A1 is stabilized by interaction with SYNV1, which prevents its proteasomal degradation. OS9 and UBE2J1 recruitment to the complex may be mediated by SEL1L (PubMed:28827405). SYNV1 assembles with SEL1L and FAM8A1 through its transmembrane domains, but interaction with its cytoplasmic domain is required to confer stability to FAM8A1 and enhance recruitment of HERPUD1 (PubMed:28827405). The HRD1 complex also associates with VIMP and may transfer misfolded proteins from the endoplasmic reticulum to VCP (PubMed:16289116). May form a complex with ERLEC1; HSPA5; OS9 AND SEL1L (PubMed:18502753, PubMed:18264092). Interacts with VCP (PubMed:16289116, PubMed:16186510). Interacts with UBXN6 (PubMed:18656546). Interacts with BAG6 (PubMed:21636303). Interacts with NFE2L1 (By similarity). Interacts (via N-terminus) with components of the pre-B cell receptor, including IGLL1 and VPREB1 (By similarity). Interacts with CREB3L3; this interaction leads to CREB3L3 ubiquitination and proteasomal degradation (By similarity).TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in liver and kidney (at protein level). Up-regulated in synovial tissues from patients with rheumatoid arthritis (at protein level).INDUCTION By endoplasmic reticulum stress-inducing agents such as thapsigargin, tunicamycin or brefeldin A, but not by heat shock.DOMAIN The RING-type zinc finger is required for E3 ligase activity.PTM Not N-glycosylated.PTM Auto-ubiquitinated.DISEASE In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), plays a role in the degradation of misfolded N-terminal mutated PRDM1 proteins.SIMILARITY Belongs to the HRD1 family.UniProtQ86TM61EQUAL617EQUALReactome Database ID Release 75535496Database 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=535496ReactomeR-HSA-5354961Reactome 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-535496.1Reactome Database ID Release 751791084Database 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=1791084ReactomeR-HSA-17910844Reactome 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-1791084.418664523Pubmed2008Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly bindsYamamoto, KSuzuki, NWada, TOkada, TYoshida, HKaufman, RJMori, KJ Biochem 144:477-86ACTIVATIONReactome Database ID Release 751791215Database 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=1791215ReactomeR-HSA-17912151Reactome 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-1791215.1LEFT-TO-RIGHTExpression of Sec12The Sec12 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13PREB geneReactome DB_ID: 5642257ENSEMBL:ENSG00000138073 PREBPREBSEC12ENSEMBLENSG00000138073Reactome Database ID Release 755642257Database 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=5642257ReactomeR-HSA-56422571Reactome 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-5642257.1PREBSec12Prolactin regulatory element-binding proteinPREB_HUMANReactome DB_ID: 203984UniProt:Q9HCU5 PREBPREBSEC12FUNCTION Guanine nucleotide exchange factor that specifically activates the small GTPase SAR1B. Mediates the recruitment of SAR1B and other COPII coat components to endoplasmic reticulum membranes and is therefore required for the formation of COPII transport vesicles from the ER.FUNCTION Was first identified based on its probable role in the regulation of pituitary gene transcription. Binds to the prolactin gene (PRL) promoter and seems to activate transcription.SUBUNIT Interacts with SAR1B (GDP-bound form) (By similarity). Interacts with MIA2; recruits PREB to endoplasmic reticulum exit sites (PubMed:25202031, PubMed:27170179).TISSUE SPECIFICITY Ubiquitous.UniProtQ9HCU51EQUAL417EQUALReactome Database ID Release 75203984Database 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=203984ReactomeR-HSA-2039841Reactome 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-203984.1Reactome Database ID Release 751791083Database 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=1791083ReactomeR-HSA-17910834Reactome 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-1791083.4ACTIVATIONReactome Database ID Release 751791217Database 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=1791217ReactomeR-HSA-17912171Reactome 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-1791217.1LEFT-TO-RIGHTExpression of Sec31AThe Sec31A gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13SEC31A geneReactome DB_ID: 5642285ENSEMBL:ENSG00000138674 SEC31ASEC31AKIAA0905SEC31L1HSPC275HSPC334ENSEMBLENSG00000138674Reactome Database ID Release 755642285Database 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=5642285ReactomeR-HSA-56422851Reactome 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-5642285.1SEC31AProtein transport protein Sec31ASC31A_HUMANReactome DB_ID: 204000UniProt:O94979 SEC31ASEC31AKIAA0905SEC31L1HSPC275HSPC334FUNCTION Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER) (PubMed:10788476). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules (By similarity).SUBUNIT COPII is composed of at least 5 proteins: the SEC23/24 complex, the SEC13/31 complex and SAR1. SEC13 and SEC31 make a 2:2 tetramer that forms the edge element of the COPII outer coat. The tetramer self-assembles in multiple copies to form the complete polyhedral cage. Interacts (via WD 8) with SEC13 (By similarity). Interacts with PDCD6; interaction takes place in response to cytosolic calcium increase and leads to bridge together the BCR(KLHL12) complex and SEC31A, leading to monoubiquitination (PubMed:27716508) (PubMed:16957052, PubMed:17196169, PubMed:27716508, PubMed:25667979). Interacts with KLHL12.TISSUE SPECIFICITY Abundantly and ubiquitously expressed.DOMAIN The ALG-2-binding site motif-2 (ABS-2) contains a PXPGF sequence that binds hydrophobic pocket 3 of PDCD6.PTM Monoubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex, leading to regulate the size of COPII coats.DISEASE A chromosomal aberration involving SEC31A is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;4)(p23;q21) with ALK.SIMILARITY Belongs to the WD repeat SEC31 family.UniProtO949791EQUAL1220EQUALReactome Database ID Release 75204000Database 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=204000ReactomeR-HSA-2040001Reactome 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-204000.1Reactome Database ID Release 751791133Database 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=1791133ReactomeR-HSA-17911334Reactome 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-1791133.4ACTIVATIONReactome Database ID Release 751791254Database 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=1791254ReactomeR-HSA-17912541Reactome 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-1791254.1LEFT-TO-RIGHTExpression of TATDN2The TATDN2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13TATDN2 geneReactome DB_ID: 5642210ENSEMBL:ENSG00000157014 TATDN2TATDN2KIAA0218ENSEMBLENSG00000157014Reactome Database ID Release 755642210Database 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=5642210ReactomeR-HSA-56422101Reactome 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-5642210.1TATDN2Putative deoxyribonuclease TATDN2TATD2_HUMANReactome DB_ID: 535508UniProt:Q93075 TATDN2TATDN2KIAA0218FUNCTION Putative deoxyribonuclease.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. TatD-type hydrolase family.UniProtQ930751EQUAL761EQUALReactome Database ID Release 75535508Database 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=535508ReactomeR-HSA-5355081Reactome 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-535508.1Reactome Database ID Release 751791156Database 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=1791156ReactomeR-HSA-17911563Reactome 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-1791156.3ACTIVATIONReactome Database ID Release 751791248Database 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=1791248ReactomeR-HSA-17912481Reactome 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-1791248.1LEFT-TO-RIGHTExpression of TPP1The TPP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13TPP1 geneReactome DB_ID: 5642252ENSEMBL:ENSG00000166340 TPP1TPP1CLN2GIG1UNQ267/PRO304ENSEMBLENSG00000166340Reactome Database ID Release 755642252Database 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=5642252ReactomeR-HSA-56422521Reactome 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-5642252.1TPP1Tripeptidyl-peptidase 1TPP1_HUMANReactome DB_ID: 535504lysosomal lumenGENE ONTOLOGYGO:0043202UniProt:O14773 TPP1TPP1CLN2GIG1UNQ267/PRO304FUNCTION Lysosomal serine protease with tripeptidyl-peptidase I activity (PubMed:11054422, PubMed:19038966, PubMed:19038967). May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases (PubMed:11054422, PubMed:19038966, PubMed:19038967). Requires substrates with an unsubstituted N-terminus (PubMed:19038966).ACTIVITY REGULATION Inhibited by diisopropyl fluorophosphate (DFP).SUBUNIT Monomer (PubMed:19038967). Interacts with CLN5 (PubMed:19941651). Interacts with CLN3 (PubMed:17237713).TISSUE SPECIFICITY Detected in all tissues examined with highest levels in heart and placenta and relatively similar levels in other tissues.PTM Activated by autocatalytic proteolytical processing upon acidification (PubMed:11054422, PubMed:19038966, PubMed:19038967). N-glycosylation is required for processing and activity (PubMed:19038966, PubMed:19038967).UniProtO14773196EQUAL563EQUALReactome Database ID Release 75535504Database 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=535504ReactomeR-HSA-5355041Reactome 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-535504.1Reactome Database ID Release 751791138Database 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=1791138ReactomeR-HSA-17911384Reactome 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-1791138.4ACTIVATIONReactome Database ID Release 751791238Database 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=1791238ReactomeR-HSA-17912381Reactome 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-1791238.1LEFT-TO-RIGHTExpression of TSPYL2The TSPYL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13TSPYL2 geneReactome DB_ID: 5642212ENSEMBL:ENSG00000184205 TSPYL2TSPYL2CDA1DENTTTSPXHRIHFB2216ENSEMBLENSG00000184205Reactome Database ID Release 755642212Database 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=5642212ReactomeR-HSA-56422121Reactome 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-5642212.1TSPYL2Testis-specific Y-encoded-like protein 2TSYL2_HUMANReactome DB_ID: 535540UniProt:Q9H2G4 TSPYL2TSPYL2CDA1DENTTTSPXHRIHFB2216FUNCTION Part of the CASK/TBR1/TSPYL2 transcriptional complex which modulates gene expression in response to neuronal synaptic activity, probably by facilitating nucleosome assembly. May inhibit cell proliferation by inducing p53-dependent CDKN1A expression.SUBUNIT Interacts with histones. Interacts with CASK. Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity).TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in brain, testis and heart, and lowest levels in liver and pancreas.INDUCTION Up-regulated in growth-arrested T-cells. Induced by TGFB1 and all-trans retinoic acid (ATRA) in lung cancer cells (at protein level).PTM Phosphorylation at Ser-20 and/or Thr-340 impairs function on cell proliferation.MISCELLANEOUS Synaptic activity down-regulates TSPYL2 protein levels by inducing rapid proteasomal degradation.MISCELLANEOUS Subject to X inactivation.SIMILARITY Belongs to the nucleosome assembly protein (NAP) family.UniProtQ9H2G41EQUAL693EQUALReactome Database ID Release 75535540Database 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=535540ReactomeR-HSA-5355401Reactome 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-535540.1Reactome Database ID Release 751791057Database 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=1791057ReactomeR-HSA-17910573Reactome 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-1791057.3ACTIVATIONReactome Database ID Release 751791233Database 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=1791233ReactomeR-HSA-17912331Reactome 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-1791233.1LEFT-TO-RIGHTExpression of Talin-1The Talin-1 (TLN1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13TLN1 geneReactome DB_ID: 5642243ENSEMBL:ENSG00000137076 TLN1TLN1KIAA1027TLNENSEMBLENSG00000137076Reactome Database ID Release 755642243Database 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=5642243ReactomeR-HSA-56422431Reactome 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-5642243.1TLN1Talin-1Reactome DB_ID: 350713UniProt:Q9Y490 TLN1TLN1KIAA1027TLNFUNCTION Probably involved in connections of major cytoskeletal structures to the plasma membrane. High molecular weight cytoskeletal protein concentrated at regions of cell-substratum contact and, in lymphocytes, at cell-cell contacts (By similarity).SUBUNIT Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with THSD1 (PubMed:27895300, PubMed:29069646); this promotes interaction with PTK2/FAK1 and VCL. Binds with high affinity to VCL and with low affinity to integrins (PubMed:15070891). Interacts with APBB1IP; this inhibits VCL binding. Interacts with PTK2/FAK1 (By similarity). Interacts with PIP5K1C and NRAP (PubMed:10320340, PubMed:12422220). Interacts with LAYN (By similarity). Interacts with SYNM (PubMed:18342854). Interacts with ITGB1; the interaction is prevented by competitive binding of ITGB1BP1 (PubMed:21768292, PubMed:12473654).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL135.UniProtQ9Y4901EQUAL2541EQUALReactome Database ID Release 75350713Database 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=350713ReactomeR-HSA-3507131Reactome 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-350713.1Reactome Database ID Release 751791137Database 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=1791137ReactomeR-HSA-17911374Reactome 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-1791137.4ACTIVATIONReactome Database ID Release 751791219Database 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=1791219ReactomeR-HSA-17912191Reactome 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-1791219.1LEFT-TO-RIGHTExpression of WFS1The WFS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13WFS1 geneReactome DB_ID: 5642303ENSEMBL:ENSG00000109501 WFS1WFS1ENSEMBLENSG00000109501Reactome Database ID Release 755642303Database 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=5642303ReactomeR-HSA-56423031Reactome 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-5642303.1WFS1WolframinWFS1_HUMANReactome DB_ID: 535474UniProt:O76024 WFS1WFS1FUNCTION Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.TISSUE SPECIFICITY Highly expressed in heart followed by brain, placenta, lung and pancreas. Weakly expressed in liver, kidney and skeletal muscle. Also expressed in islet and beta-cell insulinoma cell line.POLYMORPHISM Arg-456-His, Arg-611-His and Ile-720-Val polymorphisms are in tight linkage disequilibrium with one another and associated with type 1 diabetes in Japanese.UniProtO760241EQUAL890EQUALReactome Database ID Release 75535474Database 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=535474ReactomeR-HSA-5354741Reactome 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-535474.1Reactome Database ID Release 751791169Database 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=1791169ReactomeR-HSA-17911694Reactome 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-1791169.4ACTIVATIONReactome Database ID Release 751791205Database 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=1791205ReactomeR-HSA-17912051Reactome 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-1791205.1LEFT-TO-RIGHTExpression of WIPI1The WIPI1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13WIPI1 geneReactome DB_ID: 5642246ENSEMBL:ENSG00000070540 WIPI1WIPI1WIPI49ENSEMBLENSG00000070540Reactome Database ID Release 755642246Database 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=5642246ReactomeR-HSA-56422461Reactome 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-5642246.1WIPI1WD repeat domain phosphoinositide-interacting protein 1WIPI1_HUMANReactome DB_ID: 535609Golgi membraneGENE ONTOLOGYGO:0000139UniProt:Q5MNZ9 WIPI1WIPI1WIPI49FUNCTION Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:28561066). Plays an important role in starvation- and calcium-mediated autophagy, as well as in mitophagy (PubMed:28561066). Functions downstream of the ULK1 and PI3-kinases that produce phosphatidylinositol 3-phosphate (PtdIns3P) on membranes of the endoplasmic reticulum once activated (PubMed:28561066). Binds phosphatidylinositol 3-phosphate (PtdIns3P), and maybe other phosphoinositides including PtdIns3,5P2 and PtdIns5P, and is recruited to phagophore assembly sites at the endoplasmic reticulum membranes (PubMed:28561066). There, it assists WIPI2 in the recruitment of ATG12-ATG5-ATG16L1, a complex that directly controls the elongation of the nascent autophagosomal membrane (PubMed:28561066). Involved in xenophagy of Staphylococcus aureus. Invading S.aureus cells become entrapped in autophagosome-like WIPI1 positive vesicles targeted for lysosomal degradation. Plays also a distinct role in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy. May also regulate the trafficking of proteins involved in the mannose-6-phosphate receptor (MPR) recycling pathway.SUBUNIT Interacts with androgen receptor (AR) and the estrogen receptors ESR1 and ESR2 (PubMed:15602573). Interacts with WIPI2 (PubMed:28561066). Interacts with WDR45 (PubMed:28561066). Interacts with ATG16L1 (PubMed:28561066). May interact with NUDC (PubMed:28561066).TISSUE SPECIFICITY Ubiquitously expressed. Highly expressed in skeletal muscle, heart, testis, pancreas and placenta. Highly expressed in G361, Sk-mel-28, Sk-mel-13, WM852 and WM451 cells. Up-regulated in a variety of tumor tissues.DOMAIN The N-terminus might form a beta-propeller domain involved in specific binding to phosphatidylinositol 3,5-bisphosphate (PIP2), leading to the association of the protein to the membrane. Association to the membrane can also occur through binding to phosphatidylinositol 3-monophosphate (PI3P).SIMILARITY Belongs to the WD repeat SVP1 family.UniProtQ5MNZ91EQUAL446EQUALReactome Database ID Release 75535609Database 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=535609ReactomeR-HSA-5356091Reactome 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-535609.1Reactome Database ID Release 751791172Database 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=1791172ReactomeR-HSA-17911724Reactome 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-1791172.4ACTIVATIONReactome Database ID Release 751791235Database 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=1791235ReactomeR-HSA-17912351Reactome 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-1791235.1LEFT-TO-RIGHTExpression of YIF1AThe YIF1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13YIF1A geneReactome DB_ID: 5642286ENSEMBL:ENSG00000174851 YIF1AYIF1A54TMHYIF1PYIF1ENSEMBLENSG00000174851Reactome Database ID Release 755642286Database 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=5642286ReactomeR-HSA-56422861Reactome 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-5642286.1YIF1AProtein YIF1AYIF1A_HUMANReactome DB_ID: 535599UniProt:O95070 YIF1AYIF1A54TMHYIF1PYIF1FUNCTION Possible role in transport between endoplasmic reticulum and Golgi.SUBUNIT Interacts with YIPF5.SIMILARITY Belongs to the YIF1 family.UniProtO950702EQUAL293EQUALReactome Database ID Release 75535599Database 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=535599ReactomeR-HSA-5355991Reactome 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-535599.1Reactome Database ID Release 751791143Database 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=1791143ReactomeR-HSA-17911434Reactome 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-1791143.4ACTIVATIONReactome Database ID Release 751791234Database 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=1791234ReactomeR-HSA-17912341Reactome 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-1791234.1LEFT-TO-RIGHTExpression of ZBTB17The ZBTB17 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13ZBTB17 geneReactome DB_ID: 5642251ENSEMBL:ENSG00000116809 ZBTB17ZBTB17MIZ1ZNF151ZNF60ENSEMBLENSG00000116809Reactome Database ID Release 755642251Database 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=5642251ReactomeR-HSA-56422511Reactome 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-5642251.1ZBTB17Zinc finger and BTB domain-containing protein 17ZBT17_HUMANReactome DB_ID: 535577UniProt:Q13105 ZBTB17ZBTB17MIZ1ZNF151ZNF60FUNCTION Transcription factor that can function as an activator or repressor depending on its binding partners, and by targeting negative regulators of cell cycle progression. Plays a critical role in early lymphocyte development, where it is essential to prevent apoptosis in lymphoid precursors, allowing them to survive in response to IL7 and undergo proper lineage commitment. Has been shown to bind to the promoters of adenovirus major late protein and cyclin D1 and activate transcription. Required for early embryonic development during gastrulation. Represses RB1 transcription; this repression can be blocked by interaction with ZBTB49 isoform 3/ZNF509S1 (PubMed:25245946).SUBUNIT Homooligomerizes (via the BTB/POZ domain), multimerization is required for DNA binding. Interacts (via the C-terminal zinc fingers) with GIF1; the interaction results in the recruitment of MYB to the CDKN1A/p21 and CDKN1B promoters and repression of transcription. Interacts with TRAF2, interfering with the binding of UBC13 to TRAF2, and inhibiting TRAF2 E3 ligase activity. Interacts with MYC (via the C-terminal helix-loop-helix motif); the interaction inhibits ZBTB17 transactivation and growth arrest activities and renders it insoluble in the nucleus. Also interacts with HCFC1, MAGEA4 and TMPRSS11A. Interacts with BCL6; the interaction inhibits ZBTB17 transactivation activity on target genes involved in cell cycle arrest. Interacts with ZBTB49 isoform 3/ZNF509S1; this interaction blocks ZBTB17-mediated repression of RB1 (PubMed:25245946).TISSUE SPECIFICITY Expressed in germinal center B-cells.PTM Undergoes 'Lys-48'-linked polyubiquitination at Lys-397 and Lys-481 and subsequent proteasomal degradation in a TRAF2-dependent manner.SIMILARITY Belongs to the krueppel C2H2-type zinc-finger protein family.UniProtQ131051EQUAL803EQUALReactome Database ID Release 75535577Database 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=535577ReactomeR-HSA-5355771Reactome 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-535577.1Reactome Database ID Release 751791186Database 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=1791186ReactomeR-HSA-17911863Reactome 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-1791186.3ACTIVATIONReactome Database ID Release 751791188Database 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=1791188ReactomeR-HSA-17911881Reactome 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-1791188.1LEFT-TO-RIGHTExpression of DNAJC3 (p58IPK)The p58IPK (DNAJC3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.Authored: May, B, 2011-10-13Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31Reviewed: Urano, F, 2010-04-30Edited: May, B, 2011-10-13DNAJC3 geneReactome DB_ID: 5642211ENSEMBL:ENSG00000102580 DNAJC3DNAJC3P58IPKPRKRIENSEMBLENSG00000102580Reactome Database ID Release 755642211Database 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=5642211ReactomeR-HSA-56422111Reactome 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-5642211.1DNAJC3p58IPKReactome DB_ID: 448201UniProt:Q13217 DNAJC3DNAJC3P58IPKPRKRIFUNCTION Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Acts as a negative regulator of the EIF2AK4/GCN2 kinase activity by preventing the phosphorylation of eIF-2-alpha at 'Ser-52' and hence attenuating general protein synthesis under ER stress, hypothermic and amino acid starving stress conditions (By similarity). Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity.SUBUNIT Interacts with EIF2AK4/GCN2; this interaction occurs under endoplasmic reticulum (ER) stress, hypothermic and amino acid starving stress conditions and inhibits EIF2AK4/GCN2 kinase activity. Interacts with EIF2AK3 (By similarity). Interacts with EIF2AK2 (PubMed:8576172). Forms a trimeric complex with DNAJB1 and HSPA8 (PubMed:9920933). Interacts with THAP12 (PubMed:9447982).TISSUE SPECIFICITY Widely expressed with high level in the pancreas and testis. Also expressed in cell lines with different levels.INDUCTION Up-regulated during an endoplasmic reticulum stress via ATF6. Activated in response to infection by influenza virus through the dissociation of DNAJB1. Down-regulated by DNAJB1 and THAP12.DOMAIN The J domain mediates interaction with HSPA8.DOMAIN Binding to misfolded proteins is mediated by a hydrophobic patch forming a large groove within the first two TPR repeats.UniProtQ1321732EQUAL504EQUALReactome Database ID Release 75448201Database 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=448201ReactomeR-HSA-4482011Reactome 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-448201.1Reactome Database ID Release 751791157Database 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=1791157ReactomeR-HSA-17911574Reactome 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-1791157.48666242Pubmed1996Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor of the RNA-activated human and mouse protein kinaseKorth, MJLyons, CNWambach, MKatze, MGGene 170:181-8ACTIVATIONReactome Database ID Release 751791251Database 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=1791251ReactomeR-HSA-17912511Reactome 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-1791251.1Reactome Database ID Release 75381038Database 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=381038ReactomeR-HSA-3810383Reactome 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-381038.314559994Pubmed2003XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein responseLee, AHIwakoshi, NNGlimcher, LHMol Cell Biol 23:7448-5917612490Pubmed2007XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networksAcosta-Alvear, DZhou, YBlais, ATsikitis, MLents, NHArias, CLennon, CJKluger, YDynlacht, BDMol Cell 27:53-66Reactome Database ID Release 75381070Database 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=381070ReactomeR-HSA-3810701Reactome 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-381070.118038217Pubmed2008Endoplasmic reticulum stress responsesSchröder, MartinCell Mol Life Sci 65:862-9418048764Pubmed2008The role for endoplasmic reticulum stress in diabetes mellitusEizirik, DLCardozo, AKCnop, MEndocr Rev 29:42-6118436705Pubmed2008The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetesScheuner, DKaufman, RJEndocr Rev 29:317-33GENE ONTOLOGYGO:0036498gene ontology term for cellular processMIMI:0359