Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor
SCIE
SCOPUS
- Title
- Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor
- Authors
- Jung, KM; Tan, S; L; man, N; Petrova, K; Murray, S; Lewis, R; Kim, PK; Kim, DS; Ryu, SH; Chao, MV; Kim, TW
- Date Issued
- 2003-10-24
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLO
- Abstract
- The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent gamma-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including beta-amyloid precursor protein (APP) and Notch. A small fraction of intracellular domains derived from both APP and Notch translocates to and appears to function in the nucleus, suggesting a generic role for gamma-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75(NTR)) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75(NTR) is a multifunctional type I membrane protein that promotes neurotrophin-induced neuronal survival and differentiation by forming a heteromeric co-receptor complex with the Trk receptors. Mass spectrometric analysis revealed that gamma-secretase-mediated cleavage of p75(NTR) occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid beta-peptide 40 (Abeta40) cleavage of APP and is topologically distinct from the major TM cleavage site of Notch 1. Size exclusion chromatography and co-immunoprecipitation analyses revealed that TrkA forms a molecular complex together with either full-length p75 or membrane-tethered C-terminal fragments. The p75-ICD was not recruited into the TrkA-containing high molecular weight complex, indicating that gamma-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that gamma-secretase-mediated p75(NTR) proteolysis plays a role in the formation/disassembly of the p75-TrkA receptor complex by regulating the availability of the p75 TM domain that is required for this interaction.
- Keywords
- AMYLOID PRECURSOR PROTEIN; GROWTH-FACTOR RECEPTOR; GAMMA-SECRETASE ACTIVITY; NOTCH INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; TRUNCATED FORM; CLEAVAGE; PRESENILIN; COMPLEX; P75(NTR)
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/18287
- DOI
- 10.1074/jbc.M306028200
- ISSN
- 0021-9258
- Article Type
- Article
- Citation
- JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 43, page. 42161 - 42169, 2003-10-24
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