id: PW:0000753 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000753 title: sterol regulatory element-binding protein signaling pathway description: Sterol regulatory element-binding protein signaling pathway regulates lipid and cholesterol homeostasis via transcriptional targeting of genes such as LDL receptor and HMG-CoA reductase. HMG-CoA catalyzes the early, rate-limiting step in the cholesterol biosynthetic pathway. The sterol regulatory element binding proteins (SREBF or SREBP) represent a subfamily of basic helix-loop-helix leucine zipper transcription factors (bHLH-LZ) that have been conserved from fungi to man. In mammals, two genesencode three and in rat four isoforms. A distinguishing feature of these proteins is the presence of a conserved tyrosine residue in the DNA binding domain. The tyrosine allows for binding to direct repeat variants of the inverted repeat E-box DNA motif, the usual bHLH-LZ canonical sequence. The direct repeat is also called sterol regulatory element (SRE).The proteins also harbor a large regulatory C-terminal domain containing two membrane-spanning helices. In species from yeast to man, the domain is involved in the interaction with the WD repeat domain of Scap (SREBP cleavage-activating protein). Scap is an escort protein for the transport of Srebfs from the ER to the Golgi apparatus in response to low levels of cholesterol. In the Golgi, the Srebf proteins are cleaved sequentially by Mbtps1 and Mbtps2 proteases, respectively. The N-termini, containing the bHLH-LZ DNA-binding and dimerization, and the transactivation domains, are liberated from the membrane and translocate to the nucleus. Cholesterol or sterols regulate the translocation of Srebfs from the ER to the Golgi by promoting the interaction of Scap with the ER membrane resident proteins Insig. The binding of cholesterol to Scap or of 25-hydroxycholesterol to Insig, promotes the interaction between Scap and Insig proteins leading to subsequent sequestration of Scap-Srebf complex in the ER. The interaction probably induces conformational changes in Scap that interfere with recognition of its sorting signal by the COPII coat proteins. When cholesterol and other sterol levels are low, Scap-Insig interaction is abolished; what follows is recognition of Scap by the COPII proteins, cargo loading into COPII vesicles and translocation to the Golgi where Srebf proteins can be processed to the active form. Translocation of Srebfs to the nucleus might involve an importin-beta dependent pathway. In the nucleus Srebf(s), in co-operation with other co-regulatory factors, initiate the transcription of several genes of lipid and cholesterol metabolism and of Inisg1. Of note is the fact that at least in mammals, the Srebf pathway appears to preferentially regulate fatty acid synthesis via Srebf1c, cholesterol biosynthesis via Srebf2 and both pathways via Srebf1a. Srebf1a and Srebf1c are two transcripts derived from Srebf1 gene. diagram_image: https://rgd.mcw.edu/pathway/PW0000753/sterol%20regulatory%20element-binding%20protein%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000753/sterol%20regulatory%20element-binding%20protein%20signaling%20pathway/sterol%20regulatory%20element-binding%20protein%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000029 label: fatty acid biosynthetic pathway - id: PW:0000454 label: cholesterol biosynthetic pathway diagram_gene_links: - id: RGD:708457 label: Insig1 - id: RGD:631417 label: Insig2 - id: RGD:70935 label: Mbtps1 - id: RGD:1566171 label: Mbtps2 - id: RGD:1309378 label: Scap - id: RGD:69423 label: Srebf1 - id: RGD:1307751 label: Srebf2 diagram_chemicals: - id: PUBCHEM.COMPOUND:65094 label: 25-Hydroxycholesterol - id: PUBCHEM.COMPOUND:5997 label: cholesterol diagram_edges: - source: 25-Hydroxycholesterol relation: associated_with target: Insig2 - source: 25-Hydroxycholesterol relation: positively_affects target: Srebf at Golgi - source: Insig2 relation: associated_with target: Scap - source: Mbtps1 relation: positively_affects target: Srebf at Golgi - source: Mbtps2 relation: positively_affects target: Srebf at Golgi - source: Scap relation: associated_with target: Srebf1 - source: Scap relation: associated_with target: Srebf2 - source: Scap relation: positively_affects target: Srebf at Golgi - source: Srebf at Golgi relation: positively_affects target: translocated Srebf - source: Srebf1 relation: positively_affects target: Srebf at Golgi - source: Srebf2 relation: positively_affects target: Srebf at Golgi - source: cholesterol relation: associated_with target: Scap - source: cholesterol relation: positively_affects target: Srebf at Golgi - source: translocated Srebf relation: positively_affects target: Srebf targets - source: translocated Srebf relation: positively_affects target: cholesterol biosynthetic pathway - source: translocated Srebf relation: positively_affects target: fatty acid biosynthetic pathway diagram_labels: - Srebf at Golgi - translocated Srebf diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/srebf-targets label: Srebf targets references: - id: RGD:2317203 citation: Osborne TF and Espenshade PJ, Genes Dev. 2009 Nov 15;23(22):2578-91. - id: RGD:5129750 citation: Horton JD, etal., J Clin Invest. 2002 May;109(9):1125-31. - id: RGD:5129775 citation: Horton JD, etal., Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32. Epub 2003 Sep 25. - id: RGD:5129802 citation: Eberle D, etal., Biochimie. 2004 Nov;86(11):839-48. - id: RGD:5129865 citation: Chang TY, etal., Annu Rev Cell Dev Biol. 2006;22:129-57. - id: RGD:5129912 citation: Bengoechea-Alonso MT and Ericsson J, Curr Opin Cell Biol. 2007 Apr;19(2):215-22. Epub 2007 Feb 15. - id: RGD:5129919 citation: Sun LP, etal., Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6519-26. Epub 2007 Apr 11. - id: RGD:5129969 citation: Ikonen E Nat Rev Mol Cell Biol. 2008 Feb;9(2):125-38. - id: RGD:5130025 citation: Brown MS and Goldstein JL, J Lipid Res. 2009 Apr;50 Suppl:S15-27. Epub 2008 Oct 29. - id: RGD:5130047 citation: Shimano H FEBS J. 2009 Feb;276(3):616-21. - id: RGD:5130048 citation: Sato R FEBS J. 2009 Feb;276(3):622-7.