Ikin, Annat F, Causevic, Mirsada, Pedrini, Steve, Benson, Lyndsey S, Buxbaum, Joseph D, Suzuki, Toshiharu, Lovestone, Simon, Higashiyama, Shigeki, Mustelin, Tomas, Burgoyne, Robert D 
ORCID: 0000-0002-9219-0387 et al (show 1 more authors)
(2007)
Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding
MOLECULAR NEURODEGENERATION, 2 (1).
23-.
ISSN 1750-1326, 1750-1326
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Abstract
Background: Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbolsensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Results: Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPa. Conclusion: Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.
| Item Type: | Article |
|---|---|
| Additional Information: | 12 pages (page numbers not for citation purposes). Published: 9 December 2007. |
| Uncontrolled Keywords: | 3101 Biochemistry and Cell Biology, 31 Biological Sciences, Dementia, Aging, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Neurodegenerative, 2.1 Biological and endogenous factors |
| Subjects: | ?? R1 ?? ?? RC0321 ?? |
| Divisions: | Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 06 Jun 2008 13:06 |
| Last Modified: | 22 May 2026 19:19 |
| DOI: | 10.1186/1750-1326-2-23 |
| Publisher's Statement : | © 2007 Ikin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/673 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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