PathwayStep5186 PathwayStep5185 PathwayStep5182 PathwayStep5184 PathwayStep5183 alpha-secretase cleaves the p75NTR extracellular domain The p75NTR C-terminal fragment enters endosomes gamma-secretase cleaves the p75NTR transmembrane domain p75NTR ICD signals to NF-kB Part of the ICD migrates to the nucleus Regulated proteolysis of p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0031293 Pubmed17215246 Pubmed17986144 Reactome Database ID Release 43193692 Reactome, http://www.reactome.org ReactomeREACT_13443 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR undergoes a process of regulated intramembrane proteolysis (RIP) similar to other transmembrane proteins such as NOTCH, beta-amyloid precursor protein (APP), and ERBB4. Each of these proteins is subjected to two sequential cleavages. The first one occurs in the extracellular part of the protein and is mediated by the metalloproteinase alpha-secretase which causes shedding of the extracellular domain. The second cleavage occurs in the intramembrane region and is mediated by gamma-secretase and causes release of the intracellular domain, ICD, and of a small peptide. The ICD often traffics to the nucleus and, in some instances (e.g. NOTCH), was found to act as transcriptional regulator. Whether the p75NTR ICD does translocate to the nucleus to regulate gene expression in a way similar to the NOTCH receptor remains to be seen. The alpha- and gamma-secretase mediated cleavage of p75 appears to be regulated by neurotrophin (NGF, BDNF) binding to TRKA or TRKB. p75NTR processing also occurs in response to MAG in cerebellar granule neurons.