SREBF2 encodes sterol regulatory element-binding protein 2 (SREBP-2), a 1141-residue basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factor made as an inactive precursor inserted in the endoplasmic reticulum membrane as a hairpin of two transmembrane segments. Its C-terminal regulatory domain binds the sterol sensor SCAP. When sterols are abundant, SCAP binds INSIG proteins and the SCAP-SREBP-2 complex is held in the ER. When cellular cholesterol falls, SCAP escorts SREBP-2 in COPII vesicles to the Golgi, where site-1 protease (MBTPS1) cuts the luminal loop and site-2 protease (MBTPS2) cuts within the first transmembrane segment. This releases the N-terminal bHLH-Zip domain, which dimerizes, is imported into the nucleus by importin-beta, and binds sterol regulatory elements (SRE-1). It also binds E-box sequences. With coactivators such as CBP/p300 and the Mediator subunit MED15, nuclear SREBP-2 activates transcription of the genes for cholesterol biosynthesis (HMGCS1, HMGCR and later pathway enzymes) and uptake (LDLR), and of feedback regulators such as INSIG1 and PCSK9. This makes it the main transcriptional controller of cellular cholesterol homeostasis. The nuclear form is rapidly ubiquitinated and degraded by the proteasome. In some contexts, such as ABCA1 in endothelial cells, nuclear SREBP-2 represses transcription.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: Nuclear SREBP2 represses ABCA1 transcription in endothelial cells. Reason: Direct E-box-dependent repression of ABCA1 is shown. It is context-specific (endothelial cells) and secondary to the activator role. Supporting Evidence: PMID:15358760 Overexpression of the N terminus of SREBP2 (SREBP2(N)), an active form of SREBP2, also inhibited the ABCA1 promoter activity. PMID:15358760 The conserved E-box motif was responsible for the SREBP2(N)-mediated inhibition |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:19098903 SRF and myocardin regulate LRP-mediated amyloid-beta clearan... | KEEP AS NON CORE | Summary: SREBP2 knockdown relieves LRP1 repression in vascular smooth muscle cells. Reason: Knockdown evidence that SREBP2 is required for LRP1 downregulation downstream of MYOCD/SRF. Non-core. Supporting Evidence: PMID:19098903 silencing SREBP2 with siSREBP2 resulted in loss of LRP suppression after Ad.MYOCD gene transfer |
| GO:0000139 Golgi membrane | EXP PMID:26311497 PAQR3 modulates cholesterol homeostasis by anchoring Scap/SR... | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: PMID:26311497 when SREBP-2 was co-expressed with PAQR3, the majority of SREBP-2 was localized in the GA together with PAQR3 |
| GO:0000139 Golgi membrane | EXP PMID:28849786 SREBP-regulated lipid metabolism: convergent physiology - di... | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Golgi apparatus membrane {ECO:0000269|PubMed:26311497, ECO:0000269|PubMed:28849786} |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Golgi apparatus membrane {ECO:0000269|PubMed:26311497, ECO:0000269|PubMed:28849786} |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655842 | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: Reactome:R-HSA-1655842 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2) |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1655851 | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: Reactome:R-HSA-1655851 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2) |
| GO:0000139 Golgi membrane | TAS Reactome:R-NUL-1655840 | ACCEPT | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: The Golgi membrane is where the precursor is proteolytically activated, a defining step of SREBF2 regulation. Supporting Evidence: PMID:11994399 SREBPs lose their access to S1P and S2P in the Golgi apparatus, so their bHLH-Zip domains cannot be released from the ER membrane |
| GO:0000247 C-8 sterol isomerase activity | IDA NOT PMID:12941800 Identification and pharmacological characterization of SRBP-... | REMOVE | Summary: NOT C-8 sterol isomerase activity, from a paper on SRBP-2, an SR31747A-binding EBP-like protein. Reason: The abstract states the protein studied is a 206-residue SR31747A-binding protein homologous to the sterol isomerase HSI (EBP), named SRBP-2. It is not SREBP-2 (1141 aa), so the row is a name-collision mis-attribution stated explicitly in the abstract. SREBF2 has no isomerase domain, and the negative assertion carries no information about it. Supporting Evidence: PMID:12941800 The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. PMID:12941800 In contrast with HSI, the protein also did not exhibit detectable isomerase activity. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | KEEP AS NON CORE | Summary: TFClass-based chromatin localization for a sequence-specific TF. Reason: SREBF2 associates with promoter chromatin (ChIP at ABCA1). True, but a generic consequence of being a DNA-binding TF. Supporting Evidence: PMID:15358760 Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs. |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | MODIFY | Summary: Transcription cis-regulatory region binding from mouse ortholog transfer. Reason: Correct but general. The sequence-specific pol II cis-regulatory region term GO:0000978 is supported and already carried by the gene. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: SREBF2 binds SRE-1 and E-box sequences in RNA polymerase II promoters. Reason: Core DNA-binding activity of the nuclear form. Inherited from the SREBP clade node PTN002488844, which SREBF2 is clearly inside. Same verdict as the SREBF1 IBA row from the same node. Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. file:human/SREBF2/SREBF2-uniprot.txt Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | ACCEPT | Summary: SREBF2 binds SRE-1 and E-box sequences in RNA polymerase II promoters. Reason: EMSA and ChIP show nuclear SREBP2 binding to the ABCA1 promoter E-box and associating with the ABCA1 promoter in endothelial cells. This is pol II cis-regulatory sequence-specific binding. Supporting Evidence: PMID:15358760 sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box PMID:15358760 Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: SREBF2 is a bHLH-Zip transcription factor; its released N-terminal domain binds SRE-1 in RNA polymerase II promoters and activates cholesterol synthesis and uptake genes. Reason: Core activity. The PAINT node PTN002488844 covers the SREBP clade (human SREBF1/SREBF2, mouse and rat orthologs, fly HLH106, worm sbp-1), and SREBF2 sits well inside it; its own experimental annotations are among the descendant evidence. Same verdict as the matching SREBF1 IBA row, which descends from the same node. GO:0000981 is the level the human SREBP GO-CAM (gocams/6205c24300000880) uses, and it covers both the main activator role and the context-specific repression reported for ABCA1. Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: SREBF2 is a bHLH-Zip transcription factor; its released N-terminal domain binds SRE-1 in RNA polymerase II promoters and activates cholesterol synthesis and uptake genes. Reason: Reporter assays in HepG2 cells show nuclear SREBP-2 strongly activates promoters carrying classic SREs (HMG-CoA synthase, HMG-CoA reductase, LDLR class). Direct support for RNA polymerase II-specific DNA-binding transcription factor activity. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:12177166 SREBP-2 was inactive in spite of its ability to bind to the E-box |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:38503280 A gut-derived hormone regulates cholesterol metabolism. | ACCEPT | Summary: SREBF2 is a bHLH-Zip transcription factor; its released N-terminal domain binds SRE-1 in RNA polymerase II promoters and activates cholesterol synthesis and uptake genes. Reason: The Cholesin-GPR146 paper uses SREBP2-dependent transcription of cholesterol synthesis genes as its readout. The abstract only states SREBP2-controlled cholesterol synthesis, but the activity is well established, so the curator's full-text IDA is accepted. Supporting Evidence: PMID:38503280 inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:32497488 Mutations in SREBF1, Encoding Sterol Regulatory Element Bind... | ACCEPT | Summary: SREBF2 is a bHLH-Zip transcription factor; its released N-terminal domain binds SRE-1 in RNA polymerase II promoters and activates cholesterol synthesis and uptake genes. Reason: The cached abstract of this SREBF1 IFAP-syndrome paper does not describe SREBF2 assays, but the full text, which the curator read, may include an SREBF2 comparison. The activity is clearly correct for SREBF2, so I defer to the curator rather than second-guess it from the abstract. Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: SREBF2 is a bHLH-Zip transcription factor; its released N-terminal domain binds SRE-1 in RNA polymerase II promoters and activates cholesterol synthesis and uptake genes. Reason: TFClass places SREBF2 in the bHLH-ZIP SREBP family (1.2.6). This agrees with the experimental evidence. Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: Nuclear SREBP2 represses the ABCA1 promoter through an E-box in endothelial cells. Reason: Promoter mutation and binding data support direct E-box-dependent repression of ABCA1 by nuclear SREBP2. This is a real but context-specific activity, peripheral to the core activator role. Supporting Evidence: PMID:15358760 Overexpression of the N terminus of SREBP2 (SREBP2(N)), an active form of SREBP2, also inhibited the ABCA1 promoter activity. PMID:15358760 The conserved E-box motif was responsible for the SREBP2(N)-mediated inhibition PMID:15358760 sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IMP PMID:19098903 SRF and myocardin regulate LRP-mediated amyloid-beta clearan... | KEEP AS NON CORE | Summary: SREBP2 knockdown abolishes MYOCD/SRF-driven LRP1 suppression in vascular smooth muscle cells. Reason: The knockdown shows SREBP2 is needed for LRP1 downregulation. The paper relies on earlier work for direct repression, so this row is weaker than the ABCA1 IDA. It is kept consistent with the other rows for this term as a non-core, context-specific repressor activity. Supporting Evidence: PMID:19098903 silencing SREBP2 with siSREBP2 resulted in loss of LRP suppression after Ad.MYOCD gene transfer |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Srebf2 of DNA-binding transcription activator activity, RNA polymerase II-specific. Reason: SREBF2 is primarily a transcriptional activator of SRE-containing pol II promoters (HMGCS1, HMGCR, LDLR, INSIG1). This is the most precise MF term for the core activity. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:11994399 SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Generic DNA binding from mouse ortholog transfer. Reason: Correct but general. SREBF2 binds specific sequences (SRE-1, E-box) in pol II cis-regulatory regions, so GO:0000978 (already annotated by IBA and IDA) is the right term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. file:human/SREBF2/SREBF2-uniprot.txt Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of the generic DNA-binding transcription factor activity term. Reason: Correct but general. The RNA polymerase II-specific activator term GO:0001228, which the gene already carries, is supported by reporter-assay evidence (PMID:12177166). Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0005515 protein binding | IPI PMID:10976766 A set of proteins interacting with transcription factor Sp1 ... | REMOVE | Summary: Yeast two-hybrid screen with the SP1 activation domain retrieved an SREBP-2 fragment. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. The SP1-SREBP-2 contact is a screen hit; no specific molecular function is established by this paper. |
| GO:0005515 protein binding | IPI PMID:12855700 Sterol regulatory element-binding protein-2 interacts with h... | MODIFY | Summary: SREBP-2 interacts directly with HNF-4, which potentiates SREBP target-gene expression. Reason: The paper shows direct binding to the DNA-binding transcription factor HNF-4 and a functional co-operation at SREBP-responsive promoters, so DNA-binding transcription factor binding is a more informative term. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:12855700 The in vitro pull-down and in vivo co-immunoprecipitation experiments showed the direct interaction between SREBP-2 and HNF-4. PMID:12855700 These data provide a novel pathway by which HNF-4 potentiates the SREBP functions and stimulates expression of SREBP-responsive genes in enterohepatic cells. |
| GO:0005515 protein binding | IPI PMID:16799563 An ARC/Mediator subunit required for SREBP control of choles... | MODIFY | Summary: The SREBP activation domain binds the KIX domains of CBP/p300 (CREBBP) and Mediator subunit MED15 (ARC105), recruiting coactivators. Reason: The interaction is the mechanism by which the SREBP transactivation domain recruits coactivators. Transcription coactivator binding describes it better than bare protein binding. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:16799563 We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes PMID:16799563 Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. |
| GO:0005515 protein binding | IPI PMID:16799563 An ARC/Mediator subunit required for SREBP control of choles... | MODIFY | Summary: The SREBP activation domain binds the KIX domains of CBP/p300 (CREBBP) and Mediator subunit MED15 (ARC105), recruiting coactivators. Reason: The interaction is the mechanism by which the SREBP transactivation domain recruits coactivators. Transcription coactivator binding describes it better than bare protein binding. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:16799563 We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes PMID:16799563 Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. |
| GO:0005515 protein binding | IPI PMID:19706601 The sterol-sensing endoplasmic reticulum (ER) membrane prote... | REMOVE | Summary: SREBP-2 binds the ER sterol-sensing E3 ligase TRC8 (RNF139), forming a TRC8-SREBP-2-SCAP complex. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. TRC8 is a regulator acting on SREBP-2, not a partner through which SREBP-2 carries out a function. Supporting Evidence: PMID:19706601 TRC8 is capable of binding both SREBP-2 and SREBP cleavage-activated protein (SCAP), thereby forming a TRC8.SREBP-2.SCAP complex. |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | REMOVE | Summary: SP1 interaction from a MAP kinase interactome screen. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. High-throughput interaction data. |
| GO:0005515 protein binding | IPI PMID:22265415 Mutant p53 disrupts mammary tissue architecture via the meva... | REMOVE | Summary: Mutant p53 associates with SREBP at sterol gene promoters. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. The paper says a direct link between mutant p53 and SREBP proteins is not established. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:34819669 A multi-scale map of cell structure fusing protein images an... | REMOVE | Summary: High-throughput interactome hit (BioPlex, HuRI or multi-scale map), e.g. HLA-DPA1, FHL2 or NFYC. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. Proteome-scale interaction data; no functional consequence for SREBF2 is shown. |
| GO:0005515 protein binding | IPI PMID:9242699 Identification of complexes between the COOH-terminal domain... | REMOVE | Summary: Hamster SCAP and SREBP-2 form a complex through their C-terminal domains. Reason: Generic protein binding is uninformative. Removal does not dispute the reported interaction. The SCAP interaction is the defining feature of SREBF2 and is better captured by the SREBP-SCAP complex terms (GO:0032936, GO:0032937), which are accepted. Supporting Evidence: PMID:9242699 Co-immunoprecipitation experiments show that SCAP and SREBP-2 form a complex that can be precipitated with antibodies to either component. |
| GO:0005634 nucleus | EXP PMID:11477106 Direct demonstration of rapid degradation of nuclear sterol ... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Nuclear SREBP-2 (aa 1-481) is detected in the nucleus and is rapidly ubiquitinated and degraded by the proteasome there. Supporting Evidence: PMID:11477106 The active SREBPs translocate to the nucleus, induce the expression of responsive genes, and are degraded very rapidly. |
| GO:0005634 nucleus | EXP PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: PCK1-mediated INSIG phosphorylation releases SCAP-SREBP to the Golgi and activates SREBPs, increasing nuclear SREBP. Supporting Evidence: PMID:32322062 leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Core location of the active transcription factor. Inherited from the SREBP clade node PTN002488844. Same verdict as the SREBF1 IBA row. Supporting Evidence: PMID:8674110 The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005634 nucleus | IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Nuclear SREBP fragments are the readout of processing in this study (abstract-only cache). Supporting Evidence: PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis. |
| GO:0005634 nucleus | IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Nuclear SREBP-2 is detected by immunoblot as the product of sterol-regulated processing. Supporting Evidence: PMID:12242332 When SCAP was overexpressed, we observed the nuclear form of SREBP-2, and it did not decrease when sterols were added |
| GO:0005634 nucleus | IDA PMID:12941800 Identification and pharmacological characterization of SRBP-... | ACCEPT | Summary: From a paper on SRBP-2, an EBP-like SR31747A-binding protein, not SREBP-2. Reason: The cited paper concerns a different 206-aa protein named SRBP-2, so it does not support this row. The claim itself, that SREBF2 localizes to the nucleus, is true from independent evidence (PMID:11477106, PMID:8674110). Because rows are judged on the claim, it is accepted, and the reference problem is recorded in reference_review. Supporting Evidence: PMID:12941800 The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. PMID:11477106 The active SREBPs translocate to the nucleus, induce the expression of responsive genes, and are degraded very rapidly. |
| GO:0005634 nucleus | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Nuclear SREBP2 binds the ABCA1 promoter (ChIP) in endothelial cells. Supporting Evidence: PMID:15358760 Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs. |
| GO:0005634 nucleus | IDA PMID:19098903 SRF and myocardin regulate LRP-mediated amyloid-beta clearan... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Immunostaining shows nuclear SREBP2 in vascular smooth muscle cells. Supporting Evidence: PMID:19098903 Western blot analysis confirmed that levels of both SREBP2 cytoplasmic long form and short nuclear form were reduced |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Consistent with experimental data. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005634 nucleus | IMP PMID:32497488 Mutations in SREBF1, Encoding Sterol Regulatory Element Bind... | ACCEPT | Summary: The processed N-terminal SREBF2 fragment enters the nucleus, where it acts as a transcription factor. Reason: Abstract-only cache for this SREBF1 paper. Nuclear activity of processed SREBF2 is well established, so the curator's annotation is accepted. Supporting Evidence: PMID:8674110 The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localizes SREBF2 to the nucleoplasm. Reason: Consistent with the nuclear transcription factor form. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1655831 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: Reactome:R-HSA-1655831 The N-terminal domain of SREBP1A,1C,2 (SREBF1A,1C,2) dimerizes and is imported from the cytosol into the nucleus by importin-beta |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2065539 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2065966 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426144 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426146 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426147 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426150 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426151 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426152 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426154 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426155 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426156 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426157 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426161 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426162 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426163 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2426164 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9621400 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9621406 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9621411 | ACCEPT | Summary: Reactome places the nuclear SREBP dimer in the nucleoplasm, where it binds and activates target genes. Reason: Consistent with the nuclear transcription factor form acting at SRE-containing target genes. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Nucleus {ECO:0000269|PubMed:11477106, ECO:0000269|PubMed:32322062} |
| GO:0005737 cytoplasm | IDA PMID:12941800 Identification and pharmacological characterization of SRBP-... | MODIFY | Summary: From a paper on SRBP-2, an EBP-like SR31747A-binding protein, not SREBP-2. Reason: The cited paper studies a different protein. SREBF2 is in the cytoplasm as an ER/Golgi membrane precursor, so the claim is true but general; refine to ER membrane, consistent with the other cytoplasm rows. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12941800 The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005737 cytoplasm | IDA PMID:19098903 SRF and myocardin regulate LRP-mediated amyloid-beta clearan... | MODIFY | Summary: The SREBP2 precursor is detected in the cytoplasmic fraction ('cytoplasmic long form'). Reason: Correct but general. The cytoplasmic long form is the ER membrane-bound precursor; refine to GO:0005789. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:19098903 Western blot analysis confirmed that levels of both SREBP2 cytoplasmic long form and short nuclear form were reduced file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MODIFY | Summary: Cytoplasm, transferred from mouse Srebf2. Reason: Correct but general. Refine to ER membrane, the precursor's location. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | MODIFY | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Correct but general. The precursor is an integral membrane protein, so ER membrane (GO:0005789, already annotated) is the precise term. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005783 endoplasmic reticulum | IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | MODIFY | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Correct but general. SREBPs are retained in the ER membrane with SCAP/INSIG; refine to GO:0005789. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0005783 endoplasmic reticulum | IDA PMID:12941800 Identification and pharmacological characterization of SRBP-... | MODIFY | Summary: From a paper on SRBP-2, an EBP-like SR31747A-binding protein, not SREBP-2. Reason: The cited paper studies a different 206-aa protein, so it does not support this row. The claim (ER) is nonetheless true of SREBF2 and, like the other ER rows, is refined to ER membrane. The reference problem is recorded in reference_review. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12941800 The 1142-bp cDNA was found to encode a 206 amino acid protein not related to SRBP-1. file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-1655838 | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: PMID:11994399 they are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-1655840 | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: PMID:11994399 they are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-2317526 | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: PMID:11994399 they are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-2317528 | ACCEPT | Summary: The SREBF2 precursor is an ER membrane hairpin protein held in the ER by SCAP-INSIG when sterols are high. Reason: Core location of the precursor; the ER membrane is where sterol-regulated retention takes place. Supporting Evidence: PMID:11994399 they are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) |
| GO:0005794 Golgi apparatus | NAS PMID:23564452 Point mutation in luminal loop 7 of Scap protein blocks inte... | MODIFY | Summary: In sterol-depleted cells, SCAP escorts the SREBF2 precursor to the Golgi, where S1P and S2P cleave it in the membrane. Reason: Correct but general. SREBF2 is a membrane-embedded hairpin protein, so in the Golgi it is in the Golgi membrane (GO:0000139), which the gene already carries. Proposed replacements: Golgi membrane Supporting Evidence: PMID:23564452 Scap is a polytopic protein of the endoplasmic reticulum (ER) that controls cholesterol homeostasis by transporting sterol regulatory element-binding proteins (SREBPs) from the ER to the Golgi complex. file:human/SREBF2/SREBF2-uniprot.txt Golgi apparatus membrane {ECO:0000269|PubMed:26311497, ECO:0000269|PubMed:28849786} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655831 | KEEP AS NON CORE | Summary: Reactome places the released N-terminal fragment transiently in the cytosol, between S2P cleavage and importin-beta import. Reason: Correct as a transit location of the processed fragment. Not where SREBF2 functions. Supporting Evidence: Reactome:R-HSA-1655831 The N-terminal domain of SREBP1A,1C,2 (SREBF1A,1C,2) dimerizes and is imported from the cytosol into the nucleus by importin-beta |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655851 | KEEP AS NON CORE | Summary: Reactome places the released N-terminal fragment transiently in the cytosol, between S2P cleavage and importin-beta import. Reason: Correct as a transit location of the processed fragment. Not where SREBF2 functions. Supporting Evidence: Reactome:R-HSA-1655851 releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2065549 | KEEP AS NON CORE | Summary: Reactome places the released N-terminal fragment transiently in the cytosol, between S2P cleavage and importin-beta import. Reason: Correct as a transit location of the processed fragment. Not where SREBF2 functions. Supporting Evidence: Reactome:R-HSA-2065549 The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2065550 | KEEP AS NON CORE | Summary: Reactome places the released N-terminal fragment transiently in the cytosol, between S2P cleavage and importin-beta import. Reason: Correct as a transit location of the processed fragment. Not where SREBF2 functions. Supporting Evidence: Reactome:R-HSA-2065550 binds Importin beta-1 via the helix-loop-helix leucine zipper domain of SREBP1A,1C,2 |
| GO:0006357 regulation of transcription by RNA polymerase II | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MODIFY | Summary: Regulation of RNA polymerase II transcription. Reason: Correct but general. SREBF2 positively regulates pol II transcription of its targets, and this paper's data (INSIG1 induction) support GO:0045944, which the gene already carries. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12242332 Ponasterone A-mediated induction of nuclear SREBP-1a or SREBP-2 in these cells led to a marked increase in insig-1 mRNA |
| GO:0006629 lipid metabolic process | TAS PMID:7903453 SREBP-2, a second basic-helix-loop-helix-leucine zipper prot... | MODIFY | Summary: Lipid metabolic process. Reason: Very general. SREBP-2 regulates lipid metabolism through transcription, mainly of cholesterol synthesis and uptake genes, so GO:0045542 is the informative replacement. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. PMID:11994399 SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis |
| GO:0008203 cholesterol metabolic process | NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | MODIFY | Summary: Cholesterol metabolic process. Reason: SREBF2 is a transcription factor and controls cholesterol metabolism rather than catalysing it. The specific regulatory term GO:0045542, already accepted from experimental rows, is the better annotation. Proposed replacements: positive regulation of cholesterol biosynthetic process Supporting Evidence: PMID:11994399 SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis |
| GO:0008593 regulation of Notch signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from zebrafish srebf2 (A3KNA7), where cholesterol efflux-activated Srebp2 transactivates Notch for HSPC emergence. Reason: The zebrafish UniProt record says Srebp2 transactivates NOTCH during hematopoietic stem cell emergence (PMID:30705153). This is a developmental, target-gene-specific role and is non-core. Human evidence is lacking. |
| GO:0009267 cellular response to starvation | IMP PMID:25339898 Nutrient deprivation induces Ξ±-synuclein aggregation through... | MARK AS OVER ANNOTATED | Summary: Nutrient deprivation activates SREBP2 in a neuronal alpha-synuclein model; SREBP2 knockdown blunts downstream aggregation. Reason: SREBP2 activation under nutrient deprivation is part of the sterol-depletion response, which is already captured by the SREBP signaling pathway (a child of cellular response to sterol depletion). The knockdown phenotype (alpha-synuclein aggregation) is a downstream disease readout. It does not show SREBF2 executing a starvation response. Supporting Evidence: PMID:25339898 nutrient deprivation enhanced Ξ±-syn aggregations concomitant with significant increase of apoptosis as well as ER stress response, SREBP2 activation and cholesterolgenesis |
| GO:0010886 positive regulation of cholesterol storage | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear SREBP2 increases cellular cholesterol accumulation. Reason: Higher cellular cholesterol follows from SREBF2-driven synthesis and uptake (and, in endothelial cells, reduced ABCA1 efflux). PTN002917947 is on the SREBF2 lineage and the term is not wrong, but it describes a downstream outcome, not the core transcriptional role. Supporting Evidence: PMID:15358760 Functionally adenovirus-mediated SREBP2(N) expression increased cholesterol accumulation and decreased apoA-I-mediated cholesterol efflux. |
| GO:0010886 positive regulation of cholesterol storage | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: Nuclear SREBP2 increases cellular cholesterol accumulation. Reason: Adenoviral SREBP2(N) increases endothelial cholesterol accumulation. Same verdict as the IBA row. Supporting Evidence: PMID:15358760 Functionally adenovirus-mediated SREBP2(N) expression increased cholesterol accumulation and decreased apoA-I-mediated cholesterol efflux. |
| GO:0012507 ER to Golgi transport vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SCAP-SREBP exits the ER in COPII-coated vesicles. Reason: The SCAP-SREBF2 complex is packaged into COPII vesicles for ER-to-Golgi transport, which is the regulated step of the pathway. Supporting Evidence: PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MODIFY | Summary: Membrane, transferred from mouse Srebf2. Reason: Correct but general. The precursor is in the ER membrane and, after SCAP-mediated transport, the Golgi membrane; both are already annotated. Proposed replacements: endoplasmic reticulum membrane Golgi membrane Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038} file:human/SREBF2/SREBF2-uniprot.txt Golgi apparatus membrane {ECO:0000269|PubMed:26311497, ECO:0000269|PubMed:28849786} |
| GO:0032933 SREBP signaling pathway | IDA PMID:27614840 Sterol regulatory element-binding proteins are regulators of... | ACCEPT | Summary: SREBF2 is the transcription factor effector of the SREBP signaling pathway. Reason: SREBF2 is the ER-to-nucleus transducer that defines the SREBP signaling pathway. This paper shows that nuclear SREBP-2 binds an SRE in the NIS promoter and activates it; NIS is a non-canonical target, but the pathway role is canonical. Supporting Evidence: PMID:27614840 Gel shift assays using oligonucleotides spanning either the wild-type or the mutated SRE at -38 of the NIS 5'-flanking region showed that in vitro-translated nSREBP-1c and nSREBP-2 bind only the wild-type but not the mutated SRE at -38 of NIS. PMID:8674110 The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted SREBP signaling pathway. Reason: Correct. SREBF2 is a defining component of this pathway (PMID:8674110, PMID:12202038). Supporting Evidence: PMID:8674110 The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. PMID:12202038 In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis. |
| GO:0032933 SREBP signaling pathway | IMP PMID:27614840 Sterol regulatory element-binding proteins are regulators of... | ACCEPT | Summary: SREBF2 is the transcription factor effector of the SREBP signaling pathway. Reason: Knocking down SREBP-2 lowers expression of an SRE-containing target gene. This is consistent with the IDA row. Supporting Evidence: PMID:27614840 Knockdown of SREBP-1c and SREBP-2 by RNA interference decreased the mRNA and protein concentration of NIS by 30 to 50% |
| GO:0032936 SREBP-SCAP complex | IEA GO_REF:0000117 | ACCEPT | Summary: In the ER membrane, the SREBF2 precursor forms a complex with SCAP (via the C-terminal domains), and with INSIG when sterols are high. Reason: Consistent with experimental data (PMID:9242699). Supporting Evidence: PMID:9242699 Co-immunoprecipitation experiments show that SCAP and SREBP-2 form a complex that can be precipitated with antibodies to either component. file:human/SREBF2/SREBF2-uniprot.txt Forms a tight complex with SCAP, the SCAP-SREBP complex, in the endoplasmic reticulum membrane and the Golgi apparatus (PubMed:19706601, PubMed:26311497, PubMed:32322062). |
| GO:0032936 SREBP-SCAP complex | IPI PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | ACCEPT | Summary: In the ER membrane, the SREBF2 precursor forms a complex with SCAP (via the C-terminal domains), and with INSIG when sterols are high. Reason: SCAP-SREBP-2 complex shown by co-immunoprecipitation. The SCAP partnership is essential to SREBF2 regulation. Supporting Evidence: PMID:12242332 The coimmunoprecipitation experiment of Fig. 3 B confirms that insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols. PMID:9242699 Co-immunoprecipitation experiments show that SCAP and SREBP-2 form a complex that can be precipitated with antibodies to either component. |
| GO:0032937 SREBP-SCAP-Insig complex | IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: In the ER membrane, the SREBF2 precursor forms a complex with SCAP (via the C-terminal domains), and with INSIG when sterols are high. Reason: Sterols induce SCAP binding to INSIG-1, retaining the SCAP/SREBP complex in the ER. Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0032937 SREBP-SCAP-Insig complex | IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | ACCEPT | Summary: In the ER membrane, the SREBF2 precursor forms a complex with SCAP (via the C-terminal domains), and with INSIG when sterols are high. Reason: INSIG-2 co-immunoprecipitates SCAP and the SREBP-2 precursor in a sterol-dependent manner. Supporting Evidence: PMID:12242332 The coimmunoprecipitation experiment of Fig. 3 B confirms that insig-2 binds to the SCAP/SREBP-2 complex only in the presence of sterols. |
| GO:0032937 SREBP-SCAP-Insig complex | NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin... | ACCEPT | Summary: In the ER membrane, the SREBF2 precursor forms a complex with SCAP (via the C-terminal domains), and with INSIG when sterols are high. Reason: Same claim as the IDA row from this paper. Supporting Evidence: PMID:12202038 facilitates retention of the SCAP/SREBP complex in the ER |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IDA PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: SREBF2 activates transcription of cholesterol biosynthetic genes. Reason: Core process. Nuclear SREBP-2 strongly activates the promoters of cholesterogenic genes (HMG-CoA synthase, HMG-CoA reductase and others), raising cholesterol synthesis. This matches the human SREBP GO-CAM (gocams/6205c24300000880), where GO:0000981 is part_of GO:0045542. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c PMID:11994399 SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IDA PMID:38503280 A gut-derived hormone regulates cholesterol metabolism. | ACCEPT | Summary: SREBF2 activates transcription of cholesterol biosynthetic genes. Reason: Hepatic SREBP2-controlled cholesterol synthesis is the target of the Cholesin-GPR146-PKA axis. Supporting Evidence: PMID:38503280 inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted positive regulation of cholesterol biosynthetic process. Reason: Agrees with the experimental evidence (PMID:12177166, PMID:11994399). Supporting Evidence: PMID:11994399 SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis |
| GO:0045542 positive regulation of cholesterol biosynthetic process | IMP PMID:12177166 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 ... | ACCEPT | Summary: SREBF2 activates transcription of cholesterol biosynthetic genes. Reason: Mutating the unique bHLH tyrosine abolishes SREBP-2 transactivation of SRE promoters. This is consistent with the IDA row from the same paper. Supporting Evidence: PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of RNA polymerase II transcription by SREBF2. Reason: Activation of SRE-containing pol II promoters is the core mode of action. The IBA node PTN002917947 (vertebrate SREBF2 lineage) is sound, and SREBF2's own experimental data are among its descendant evidence. Supporting Evidence: PMID:7903453 In vitro SREBP-2 bound SRE-1 with the same specificity as SREBP-1a. In vivo it mimicked SREBP-1a in activating transcription of reporter genes containing SRE-1. PMID:12177166 cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S... | ACCEPT | Summary: Positive regulation of RNA polymerase II transcription by SREBF2. Reason: Induction of nuclear SREBP-2 increases INSIG1 mRNA, which is the sterol feedback loop. Supporting Evidence: PMID:12242332 Ponasterone A-mediated induction of nuclear SREBP-1a or SREBP-2 in these cells led to a marked increase in insig-1 mRNA |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12446768 Expression of a novel, sterol-insensitive form of sterol reg... | ACCEPT | Summary: A germ-cell SREBP2 isoform (SREBP2gc) is a soluble, constitutively active transcription factor. Reason: Rat/mouse spermatogenic SREBP2gc activates SRE-containing promoters without sterol feedback. The activity is the canonical pol II activator function. Supporting Evidence: PMID:12446768 This protein, SREBP2gc, is expressed in a stage-dependent fashion as a soluble, constitutively active transcription factor that is not subject to feedback control by sterols. |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro bHLH/bHLH-Zip domain mapping to protein dimerization activity. Reason: The bHLH-Zip domain mediates homodimerization of the nuclear form, which is needed for DNA binding and importin-beta-dependent import (Reactome R-HSA-2065549). True, but supporting rather than core. Supporting Evidence: Reactome:R-HSA-2065549 The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize via interaction of their helix-loop-helix leucine zipper domains |
| GO:0070888 E-box binding | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: Nuclear SREBP2 binds consensus and ABCA1 E-box sequences. Reason: E-box binding is a genuine dual specificity of the SREBP bHLH domain (a tyrosine in the basic region allows SRE-1 binding). For SREBP-2, however, E-box binding does not lead to activation (PMID:12177166), and the ABCA1 E-box case is repression. The core specificity is SRE-1. Supporting Evidence: PMID:15358760 sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box PMID:12177166 SREBP-2 was inactive in spite of its ability to bind to the E-box file:human/SREBF2/SREBF2-uniprot.txt Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). |
| GO:0071404 cellular response to low-density lipoprotein particle stimulus | IEP PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: SREBP2 activity responds to cellular sterol status. Reason: SREBP-2 processing is suppressed by LDL-derived cholesterol and activated by sterol depletion, so a response to LDL is a genuine feature of its regulation. The IEP evidence is expression-based and the term is peripheral. Supporting Evidence: PMID:15358760 sterol depletion activated SREBP2 and increased its target, low density lipoprotein receptor mRNA |
| GO:0071499 cellular response to laminar fluid shear stress | NAS PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | MARK AS OVER ANNOTATED | Summary: Cellular response to laminar fluid shear stress. Reason: The cached abstract reports that oscillatory flow, not laminar flow, activated SREBP2 in endothelial cells. A response to laminar shear is not supported by the available text, and the NAS evidence is weak. Supporting Evidence: PMID:15358760 oscillatory flow caused the activation of SREBP2 and therefore attenuated ABCA1 promoter activity in ECs |
| GO:0090370 negative regulation of cholesterol efflux | IDA PMID:15358760 Sterol-responsive element-binding protein (SREBP) 2 down-reg... | KEEP AS NON CORE | Summary: Nuclear SREBP2 decreases apoA-I-mediated cholesterol efflux by repressing ABCA1. Reason: Supported by the abstract; acts through ABCA1 repression. Non-core. Supporting Evidence: PMID:15358760 Functionally adenovirus-mediated SREBP2(N) expression increased cholesterol accumulation and decreased apoA-I-mediated cholesterol efflux. PMID:15358760 Overexpression of the N terminus of SREBP2 (SREBP2(N)), an active form of SREBP2, also inhibited the ABCA1 promoter activity. |
| GO:1900222 negative regulation of amyloid-beta clearance | IMP PMID:19098903 SRF and myocardin regulate LRP-mediated amyloid-beta clearan... | MARK AS OVER ANNOTATED | Summary: In this model, SREBP2-mediated LRP1 repression in cerebral VSMCs reduces amyloid-beta clearance. Reason: This is a distal consequence of LRP1 repression. SREBF2 does no step of amyloid-beta clearance; it lowers expression of the receptor that does. The knockdown shows necessity in this cell-type context, not participation, so the process term overstates SREBF2's role. Supporting Evidence: PMID:19098903 silencing SREBP2 with siSREBP2 resulted in loss of LRP suppression after Ad.MYOCD gene transfer |
| GO:1901524 regulation of mitophagy | HMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | MARK AS OVER ANNOTATED | Summary: Genome-wide RNAi screen for regulators of Parkin translocation and mitophagy. Reason: The paper's validated hit is SREBF1, and the cached text does not discuss SREBF2. A screen hit of this kind most likely reflects a lipid-supply requirement, not a role in mitophagy regulation. |
| GO:1902895 positive regulation of miRNA transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of miRNA transcription, transferred from mouse Srebf2. Reason: SREBP-2 can activate miRNA genes with SRE-containing promoters (from the mouse annotation). The term is plausible but peripheral to cholesterol-gene activation. |
| GO:1903749 obsolete positive regulation of protein localization to mitochondrion | HMP PMID:24912190 Genome-wide RNAi screen identifies the Parkinson disease GWA... | MARK AS OVER ANNOTATED | Summary: Screen-based term (now obsolete) for positive regulation of protein localization to mitochondrion. Reason: Same screen as the mitophagy row. SREBF2 is not discussed in the cached text, and the term is obsolete in current GO. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | MODIFY | Summary: HT-SELEX (methyl-SELEX) profiling of human TF DNA-binding specificity included SREBF2. Reason: True, but generic sequence-specific dsDNA binding. SREBF2's established binding sites are SRE-1 and E-box elements in pol II promoters, so GO:0000978 (already carried by IBA and IDA) is the better term. The cached text of this large screen does not discuss SREBF2 individually. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:human/SREBF2/SREBF2-uniprot.txt Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:12177166, PubMed:7903453). |
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Download this section (compressed HTML)Q: How is SREBP-2 processing kept sterol-sensitive while SREBP-1a processing escapes sterol control in fatty-acid-depleted cells, if both are carried by the same SCAP?
Q: Does nuclear SREBP-2 repress genes such as ABCA1 and LRP1 directly through E-box binding in vivo, or are these effects mainly secondary to changes in sterol status and LXR activity?
Q: Should the substrate role of SREBF2 in S1P/S2P-mediated regulated intramembrane proteolysis be captured as has_input on the protease activities in GO-CAM, rather than as a process annotation on SREBF2?
Experiment: In endothelial and vascular smooth muscle cells with endogenous SREBF2 replaced by DNA-binding-dead or SRE-only (bHLH tyrosine-to-arginine) variants, combine CUT&RUN for nuclear SREBP-2 with promoter E-box editing and nascent-transcript measurement, holding cellular sterol constant with LXR agonist/antagonist controls.
Hypothesis: SREBP-2 repression of ABCA1 and LRP1 is a direct, E-box-dependent activity of the nuclear form.
Type: Genome editing with chromatin occupancy and nascent transcription assays
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