Tumour Necrosis Factor Alpha-converting Enzyme Mediates Ectodomain Shedding of Vps10p-domain Receptor Family Members.
From: Institute of Medical Biochemistry, MIND Center, Ole Worms Allé, Building 1170, University of Aarhus, 8000 Arhus C, Denmark.
The Biochemical journal
- Publish Date: Apr 2006
- ISSN: 1470-8728
- Volume: 395
- Issue: 2
- Pages: 285-93
- Medium: Internet
- Language: English
- Citation (JAMA): Hermey Guido, Sjøgaard Susanne S, Petersen Claus Munck, et al. Tumour Necrosis Factor Alpha-converting Enzyme Mediates Ectodomain Shedding of Vps10p-domain Receptor Family Members.. Biochem. J. Apr 2006;395:285-93
Abstract
Several transmembrane molecules are cleaved at juxtamembrane extracellular sites leading to shedding of ectodomains. We analysed shedding of members of the Vps10p-D (Vps10p domain; where Vps is vacuolar protein sorting) family of neuronal type-I receptors with partially overlapping functions, and additional proteolytic events initiated by the shedding. When transfected into CHO (Chinese-hamster ovary) cells (CHO-K1), sorCS1a-sorCS1c isoforms were shed at high rates (approximately 0.61% x min(-1)) that were increased approx. 3-fold upon stimulation with phorbol ester. sorCS1c identified in the cultured neuroblastoma cell line SH-SY5Y was shed similarly. In CHO-K1 transfectants, constitutive and stimulated shedding of sorCS3 also occurred at high rates (0.29% and 1.03% x min(-1)). By comparison, constitutive and stimulated shedding of sorLA occurred at somewhat lower rates (0.07% and 0.48% x min(-1)), whereas sorCS2 and sortilin were shed at very low rates even when stimulated (approximately 0.01% x min(-1)). Except for sorCS2, shedding of the receptors was dramatically reduced in mutant CHO cells (CHO-M2) devoid of active TACE (tumour necrosis factor alpha-converting enzyme), demonstrating that this enzyme accounts for most sheddase activity. The release of sorCS1 and sorLA ectodomains initiated rapid cleavage of the membrane-tethered C-terminal stubs that accumulated only in the presence of gamma-secretase inhibitors. Purified shed sorLA bound several ligands similarly to the entire luminal domain of the receptor, including PDGF-BB (platelet-derived growth factor-BB) and amyloid-beta precursor protein. In addition, PDGF-BB also bound to the luminal domains of sorCS1 and sorCS3. The results suggest that ectodomains shed from a subset of Vps10p-D receptors can function as carrier proteins.
Mesh Headings (Keywords): ADAM Proteins, Amino Acid Sequence, Animals, CHO Cells, Cells, Cultured, Cricetinae, Humans, LDL-Receptor Related Proteins, Ligands, Membrane Glycoproteins, Membrane Transport Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Protein Isoforms, Protein Processing, Post-Translational, Receptors, Cell Surface, Receptors, LDL, Receptors, Neuropeptide, Vesicular Transport Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16393139
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