PathwayStep1512 PathwayStep1469 PathwayStep1468 PathwayStep1467 PathwayStep1466 PathwayStep1465 PathwayStep1473 PathwayStep1474 PathwayStep1471 PathwayStep1472 PathwayStep1470 SREBP1A/1C/2 Dimerizes SREBP1A/1C/2 Binds Importin beta-1 S2P Cleaves SREBP1A/1C/2 SREBP1A/1C/2 Dissociates from Importin beta-1 SREBP1A/1C/2 Transits to the Nucleus SREBP1A/1C/2:SCAP Transits to the Golgi SREBP1A/1C/2:SCAP Binds CopII Coat Complex SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:INSIG:oxysterol SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG S1P Cleaves SREBP1A/1C/2 Activation of Gene Expression by SREBP (SREBF) Regulation of Cholesterol Biosynthesis by SREBP (SREBF) Authored: May, B, 2011-09-28 Edited: May, B, 2011-10-13 Pubmed15457548 Pubmed18974038 Pubmed19933148 Reactome Database ID Release 431655829 Reactome, http://www.reactome.org ReactomeREACT_147797 Reviewed: Liang, Guosheng, 2012-08-25 Sterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis (reviewed in Brown and Goldstein 2009, Osborne and Espenshade 2009, Weber et al. 2004).<br> Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.<br>In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis.