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

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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) and Gandy, Sam (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-.

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Abstract

<h4>Background</h4>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 alpha-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 phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1.<h4>Results</h4>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 sAPPalpha.<h4>Conclusion</h4>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:	Alzheimer amyloid precursor protein, APP, phorbol esters, protein kinase C, PKC, phorbol-binding proteins, shedding, trans-Golgi network, TGN, α-secretase(s), phospho-state-sensitive modulators of ectodomain shedding, PMES, phorbolsensitive proteins
Subjects:	?? R1 ?? ?? RC0321 ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	06 Jun 2008 13:06
Last Modified:	16 Dec 2022 04:00
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.
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URI:	https://livrepository.liverpool.ac.uk/id/eprint/673