FUNCTION Escort protein required for cholesterol as well as lipid homeostasis. Regulates export of the SCAP/SREBF complex from the ER upon low cholesterol. Formation of a ternary complex with INSIG at high sterol concentrations leads to masking of an ER-export signal in SCAP and retention of the complex in the ER. Low sterol concentrations trigger release of INSIG, a conformational change in the SSC domain of SCAP, unmasking of the ER export signal, recruitment into COPII-coated vesicles, transport to the Golgi complex, proteolytic cleavage of SREBF in the Golgi, release of the transcription factor fragment of SREBF from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway.DOMAIN Cholesterol bound to SSC domain of SCAP or oxysterol bound to INSIG1/2 leads to masking of an ER export signal on SCAP possibly by moving the signal further away from the ER membrane.DISRUPTION PHENOTYPE CHO cells show loss of site-1 cleavage of SREBF1/2, reduced synthesis of cholesterol, a reduced level of LDLR and cholesterol auxotrophy.SIMILARITY Belongs to the WD repeat SCAP family.SIMILARITY Contains 1 SSD (sterol-sensing) domain.SIMILARITY Contains 7 WD repeats.
FUNCTION Mediates feedback control of cholesterol synthesis by controlling SCAP and HMGCR. Functions by blocking the processing of sterol regulatory element-binding proteins (SREBPs). Capable of retaining the SCAP-SREBF2 complex in the ER thus preventing it from escorting SREBPs to the Golgi. Initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase, AMFR/gp78. May play a role in growth and differentiation of tissues involved in metabolic control. May play a regulatory role during G0/G1 transition of cell growth.SUBUNIT Binds to the SCAP-SREBF2 complex only in the presence of sterols. Interacts with RNF139. Interacts with HMGCR (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at the ER membrane for its ubiquitination and degradation by the sterol-mediated ERAD pathway.TISSUE SPECIFICITY Expressed in all tissues tested with highest expression in the liver.INDUCTION By insulin.PTM Ubiquitinated. Subsequent to sterol deprivation, the SCAP-SREBF2 complex becomes dissociated from INSIG1, is then ubiquitinated and degraded in proteasomes. Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex. Ubiquitinated by RNF139.MISCELLANEOUS Expressed at high levels when nuclear SREBP levels are high as a result of sterol deprivation.SIMILARITY Belongs to the INSIG family.
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Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14
In the endoplasmic reticulum, Notch receptor precursors are fucosylated on conserved serine and threonine residues in their EGF repeats. The consensus fucosylation site sequence is C2-X(4-5)-S/T-C3, where C2 and C3 are the second and third cysteine residue within the EGF repeat, and X(4-5) is four to five amino acid residues of any type. Only those fucosylation sites that are conserved between human, mouse and rat Notch isoforms are annotated. Fucosylation is performed by the endoplasmic reticulum resident O-fucosyl transferase POFUT1. Fucosylation by POFUT1, initially discovered in Drosophila, is considered to be an essential step in Notch processing and production of a fully functional receptor. Fucosylation of mammalian Notch proteins was studied by exogenously expressing mouse Notch1 in Chinese hamster ovary cell lines.
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In low concentrations of cholesterol SCAP interacts with Sec24 of the CopII coat complex causing SCAP:SREBP1A/1C/2 to be transported with the CopII complex from the endoplasmic reticulum to the Golgi.
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SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG
SREBPs (SREBP1A/1C/2, SREBFs) bind SCAP in the endoplasmic reticulum membrane. Luminal loop 1 of SCAP binds cholesterol (Adams et al. 2003) which prevents SCAP from interacting with Sec24 in the CopII coat complex and allows SCAP to interact with INSIG instead (Sakai et al. 1997, Yang et al. 2002, Dobrosotskaya et al. 2003, Adams et al. 2004, Feramisco et al. 2005, Sun et al. 2005). These interactions retain SCAP:SREBP1A/1C/2 in the endoplasmic reticulum.
Using Chinese hamster (Cricetulus griseus) ovary cells that express endogenous Notch1 but do not express endogenous Fringe proteins, Moloney et al. found after introduction of mouse Mfng that mature Notch1 had the Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol tetrasaccharide attached to conserved serine and threonine residues in EGF repeats of Notch1 (Moloney et al. 2000). Sialyltransferases that could be involved in formation of this type of tetrasaccharide are St3gal3, St3gal4 and St3gal6 (Harduin-Lepers et al. 2001).
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SREBP2 (SREBF2 and by inference SREBP1A and SREBP1C) is a transmembrane protein that binds SCAP in the endoplasmic reticulum membrane (Sakai et al. 1997). In the presence of cholesterol or oxysterols SCAP:SREBP2 binds INSIG and is retained in the endoplasmic reticulum (Espenshade et al. 2002, Yabe et al. 2002, Yang et al. 2002, Adams et al. 2003, Dobrosotskaya et al. 2003, Adams et al. 2004, Radhakrishnan et al. 2004, Sun et al. 2005, Sun et al. 2007, Motamed et al. 2011). At cholesterol concentrations below 5 mol% SCAP changes conformation, SCAP:SREBP2 loses interaction with INSIG, binds the CopII coat complex, and is translocated to the Golgi (Adams et al 2004, Feramisco et al. 2005, Radhakrishnan et al. 2008, Motamed et al. 2011).
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SREBP2 (SREBF2) is retained in the endoplasmic reticulum by SCAP:INSIG2:oxysterol
INSIG binds oxysterols and the INSIG:oxysterol complex interacts with SCAP subunits of the SREBP2:SCAP (SREBF2:SCAP) complex (Adams et al. 2004, Radhakrishnan et al. 2007). This interaction retains the SREBP2:SCAP:INSIG:oxysterol complex in the endoplasmic reticulum. From this reaction it is inferred that SREBP1A (SREBF1A) and SREBP1C (SREBF1C) are retained similarly.
Using Chinese hamster (Cricetulus griseus) ovarian cell lines deficient in different galactosyltransferases, Chen et al. established that beta-4-galactosyltransferase 1 (B4galt1) was necessary for galactosylation of beta 1,3-linked N-acetylglucosaminyl group added by fringe enzymes to O-linked fucosyl residues on Notch1. B4galt1-mediated galactosylation of Notch1 was necessary for fringe-induced modulation of Notch1 signaling. Since the genome of C. griseus has not been completely sequenced, it is possible that annotated C. griseus Notch isoforms do not represent full-length proteins. Annotated C. griseus Notch2 in particular seems truncated. Only those fucosylation and glycosylation sites that are conserved between Chinese hamster, mouse, human and rat are shown. Since the exact preference, if any, of fringe enzymes for Notch O-fucose sites is not known, the extension of an O-fucosyl residue at an unknown position is shown.
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Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER
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FUNCTION Component of the COPII coat, that covers ER-derived vesicles involved in transport from the endoplasmic reticulum to the Golgi apparatus. COPII acts in the cytoplasm to promote the transport of secretory, plasma membrane, and vacuolar proteins from the endoplasmic reticulum to the Golgi complex.SUBUNIT Interacts with SLC6A4 (By similarity). COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1. SEC24C is capable of forming heterodimers with SEC24A. Interacts with TMED2 and TMED10.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the SEC23/SEC24 family. SEC24 subfamily.
Sterol regulatory element-binding protein 2
FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). May play a role during CNS development.SUBUNIT Interacts with PSMA1 (By similarity). Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with HIF1AN.TISSUE SPECIFICITY Proliferating neuroepithelium.DEVELOPMENTAL STAGE CNS development.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family.SIMILARITY Contains 5 ANK repeats.SIMILARITY Contains 34 EGF-like domains.SIMILARITY Contains 3 LNR (Lin/Notch) repeats.
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Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro
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FUNCTION Transcriptional activator required for lipid homeostasis. Regulates transcription of the LDL receptor gene as well as the cholesterol and to a lesser degree the fatty acid synthesis pathway (By similarity). Binds the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3') found in the flanking region of the LDRL and HMG-CoA synthase genes.SUBUNIT Forms a tight complex with SCAP in the ER membrane. Efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein. Interacts with LMNA. Component of SCAP/SREBP complex composed of SREBF2, SCAP and RNF139; the complex hampers the interaction between SCAP and SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts (via C-terminus domain) with RNF139.TISSUE SPECIFICITY Ubiquitously expressed in adult and fetal tissues.PTM At low cholesterol the SCAP/SREBP complex is recruited into COPII vesicles for export from the ER. In the Golgi complex SREBPs are cleaved sequentially by site-1 and site-2 protease. The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain and releases the transcription factor from the Golgi membrane. Apoptosis triggers cleavage by the cysteine proteases caspase-3 and caspase-7.SIMILARITY Belongs to the SREBP family.SIMILARITY Contains 1 bHLH (basic helix-loop-helix) domain.
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Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein
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Chaperone activity of protein O-fucosyltransferase 1 promotes notch receptor folding
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Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins
Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region
At the time of annotation, only a fragment of this protein was annotated in UniProt, under P83337
Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain
FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). May regulate branching morphogenesis in the developing vascular system.SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4.TISSUE SPECIFICITY Highly expressed in lung, moderately in heart kidney, and at lower levels in the ovary and skeletal muscle. A very low expression is seen in the brain, intestine, liver and testis.DEVELOPMENTAL STAGE Highly expressed in endothelial cells during embryonic development from 9.0 dpc.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.DISEASE Note=Loss of the extracellular domain causes constitutive activation of the Notch protein, which leads to hyperproliferation of glandular epithelial tissues and development of mammary carcinomas.SIMILARITY Belongs to the NOTCH family.SIMILARITY Contains 5 ANK repeats.SIMILARITY Contains 29 EGF-like domains.SIMILARITY Contains 3 LNR (Lin/Notch) repeats.
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FUNCTION Mediates feedback control of cholesterol synthesis by controlling SCAP and HMGCR. Functions by blocking the processing of sterol regulatory element-binding proteins (SREBPs). Capable of retaining the SCAP-SREBF2 complex in the ER thus preventing it from escorting SREBPs to the Golgi. Seems to regulate the ubiquitin-mediated proteasomal degradation of HMGCR.SUBUNIT Binds to the SCAP-SREBF2 complex only in the presence of sterols. Interacts with RNF139.MISCELLANEOUS Does not require nuclear SREBPs for its expression. When nuclear SREBP activity is low, is the only form of INSIG present in the cell.SIMILARITY Belongs to the INSIG family.
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Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles
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Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase
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Identification of luminal Loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis
Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins
Fringe is a glycosyltransferase that modifies Notch
Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs
Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance
Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig
Proc. Natl. Acad. Sci. U.S.A. 104:6511-8
SUBUNIT COPII is composed of at least five proteins: the Sec23/24 complex, the Sec13/31 complex and Sar1. Interacts with SEC23IP. Interacts with HTR4. Interacts with SEC16A (By similarity). Interacts with SLC6A4.TISSUE SPECIFICITY High levels in brain and fibroblasts.SIMILARITY Belongs to the SEC23/SEC24 family. SEC23 subfamily.
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FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation.SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2. Interacts with RELA/p65. Interacts with HIF1AN.TISSUE SPECIFICITY Expressed in the brain, liver, kidney, neuroepithelia, somites, optic vesicles and branchial arches, but not heart.DEVELOPMENTAL STAGE Expressed in the embryonic ventricular zone, the postnatal ependymal cells, and the choroid plexus throughout embryonic and postnatal development.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family.SIMILARITY Contains 6 ANK repeats.SIMILARITY Contains 35 EGF-like domains.SIMILARITY Contains 3 LNR (Lin/Notch) repeats.
Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1
FUNCTION Involved in transport from the endoplasmic reticulum to the Golgi apparatus. Activated by the guanine nucleotide exchange factor PREB. Involved in the selection of the protein cargo and the assembly of the COPII coat complex.SUBUNIT Homodimer. Binds PREB. Part of the COPII coat complex. Binds to the cytoplasmic tails of target proteins in the endoplasmic reticulum.SIMILARITY Belongs to the small GTPase superfamily. SAR1 family.
Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions
FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May enhance HIF1A function by sequestering HIF1AN away from HIF1A.TISSUE SPECIFICITY Highly expressed in the brain, lung and thymus. Expressed at lower levels in the spleen, bone-marrow, spinal cord, eyes, mammary gland, liver, intestine, skeletal muscle, kidney and heart. In the hair follicle, highly expressed exclusively in the epithelial compartment.DEVELOPMENTAL STAGE First detected in the mesoderm at 7.5 dpc By 8.5 dpc highly expressed in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels are seen in the neuroepithelium. Between 9.5-10.5 dpc expressed at high levels in the neuroepithelium. At 13.5 dpc expressed in the surface ectoderm, eye and developing whisker follicles. Hair follicle matrix cells expression starts as different cell types become distinguishable in the developing follicle. Expression persists throughout the growth phase of the follicle and maintains the same expression profile in the second hair cycle. The cells in the follicle that undergo a phase of high level expression are in transition from mitotic precursors to several discrete, differentiating cell types. Specifically expressed in cerebellar Bergmann glial cells during postnatal development.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). Following endocytosis, this fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Ubiquitinated; undergoes 'Lys-29'-linked polyubiquitination catalyzed by ITCH. Monoubiquitination at Lys-1749 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch.PTM Hydroxylated at Asn-1945 and Asn-2012 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD.SIMILARITY Belongs to the NOTCH family.SIMILARITY Contains 5 ANK repeats.SIMILARITY Contains 36 EGF-like domains.SIMILARITY Contains 3 LNR (Lin/Notch) repeats.
Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs
Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER
Roles of Pofut1 and O-fucose in mammalian Notch signaling
Intramembrane aspartic acid in SCAP protein governs cholesterol-induced conformational change
FUNCTION Transcriptional activator required for lipid homeostasis. Regulates transcription of the LDL receptor gene as well as the fatty acid and to a lesser degree the cholesterol synthesis pathway (By similarity). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3').SUBUNIT Forms a tight complex with SCAP in the ER membrane. Efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein. Interacts with LMNA.TISSUE SPECIFICITY Expressed in a wide variety of tissues, most abundant in liver and adrenal gland. In fetal tissues lung and liver shows highest expression. Isoform SREBP-1C predominates in liver, adrenal gland and ovary, whereas isoform SREBP-1A predominates in hepatoma cell lines. Isoform SREBP-1A and isoform SREBP-1C are found in kidney, brain, white fat, and muscle.PTM At low cholesterol the SCAP/SREBP complex is recruited into COPII vesicles for export from the ER. In the Golgi complex SREBPs are cleaved sequentially by site-1 and site-2 protease. The first cleavage by site-1 protease occurs within the luminal loop, the second cleavage by site-2 protease occurs within the first transmembrane domain and releases the transcription factor from the Golgi membrane. Apoptosis triggers cleavage by the cysteine proteases caspase-3 and caspase-7.SIMILARITY Belongs to the SREBP family.SIMILARITY Contains 1 bHLH (basic helix-loop-helix) domain.
Sterol regulatory element-binding protein 1A
Sterol regulatory element-binding protein 1C
gene ontology term for cellular function
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