title: Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability.
abstract: The 75 kDa neurotrophin receptor (p75NTR) and two neurotrophin receptor homologs (NRH1, NRH2) constitute a subfamily of the nerve growth factor/tumor necrosis factor receptor superfamily. NRH1 coexists with p75NTR in fish, amphibians, and birds but is absent in mammals, whereas NRH2 exists only in mammals. Unlike p75NTR and NRH1, NRH2 lacks a canonical extracellular ligand binding domain. The similarity of NRH2 to the product of metalloproteinase cleavage of p75NTR prompted us to examine the cleavage of p75NTR in greater detail. p75NTR, NRH1, and NRH2 undergo multiple proteolytic cleavages that ultimately release cytoplasmic fragments. For p75NTR, cleavage in the extracellular domain by a PMA-inducible membrane metalloproteinase is followed by cleavage within or near the transmembrane domain, releasing the intracellular domain into the cytoplasm. This processing resembles the alpha- and gamma-secretase-mediated processing of beta-amyloid precursor protein and the similar processing of Notch. Although neurotrophins did not regulate p75NTR processing, the alpha- and gamma-secretase-mediated cleavage of p75 is modulated by receptor tyrosine kinases (Trks) TrkA and TrkB but not TrkC. Surprisingly, although NRH1 and NRH2 also undergo proteolytic cytoplasmic release of intracellular domains, a different protease mediates the cleavage. Furthermore, whereas the p75NTR soluble intracellular domain accumulates only in the presence of proteasome inhibitors, the equivalent fragment of NRH2 is stable and localizes in the nucleus. Because soluble intracellular domains of p75NTR and NRH2 were found to activate NF-kappaB in concert with TNF receptor associated factor 6 (TRAF6), we propose that cleavage of these proteins may serve conserved cytoplasmic and nuclear signaling functions through distinct proteases.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kanning
authors.forename: Mark
authors.initials: M
authors.lastname: Hudson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Amieux
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Wiley
authors.forename: Mark
authors.initials: M
authors.lastname: Bothwell
authors.forename: Leslayann C
authors.initials: LC
authors.lastname: Schecterson
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016282:Aspartic Acid Endopeptidases; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D014981:Xenopus
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; C476127:NRH1 protein, Xenopus; C476128:NRH2 protein, mouse; C470601:Nradd protein, rat; D010446:Peptide Fragments; D011506:Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D048029:TNF Receptor-Associated Factor 6; D004441:Ecdysterone; C008999:ponasterone A; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse