HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 45, 47101-47108, November 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/45/47101    most recent M408474200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khvotchev, M. Articles by Südhof, T. C. Search for Related Content PubMed PubMed Citation Articles by Khvotchev, M. Articles by Südhof, T. C. Social Bookmarking                      What's this?

Proteolytic Processing of Amyloid- Precursor Protein by Secretases Does Not Require Cell Surface Transport^*

Mikhail Khvotchev and Thomas C. Südhof

From the Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111

Cleavage of amyloid- precursor protein (APP) by -,-, and -secretases releases an extracellular fragment called APP_S, small A peptides, and a short APP intracellular domain that may provide a transcriptional signal analogous to the Notch intracellular domain. Notch cleavage is activated by extracellular ligands on the cell surface, but the cellular localization of APP cleavage remains unclear. We now show that in transfected cultured cells, the plasma membrane SNARE protein syntaxin 1A, when expressed as a full-length protein, disrupts the Golgi apparatus and blocks trans-Golgi traffic and exocytosis. In contrast, truncated syntaxin 1A^1–243 selectively abolishes exocytosis but has no apparent effect on trans-Golgi traffic or Golgi structure, whereas further truncated syntaxins 1A^1–236 and 1A^1–230 have no effect on either exocytosis or Golgi traffic. Using these syntaxin 1A fragments, we demonstrated that blocking trans-Golgi traffic greatly impairs APP cleavage and AICD-dependent nuclear signaling, whereas blocking exocytosis alone does not affect either process, even though secretion of APP_S and A40 peptide is abolished. Our data suggest that, different from Notch, cleavage of APP is independent of cell surface regulation by extracellular ligands but may be controlled by intracellular signaling.

Received for publication, July 27, 2004 , and in revised form, August 12, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Basic Neuroscience, Dept. of Molecular Genetics, and Howard Hughes Medical Inst., The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd. NA4.118, Dallas, TX 75390-9111. Tel.: 214-648-1876; Fax: 214-648-1879; E-mail: Thomas.Sudhof{at}UTSouthwestern.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Schmidt, A. Sporbert, M. Rohe, T. Reimer, A. Rehm, O. M. Andersen, and T. E. Willnow SorLA/LR11 Regulates Processing of Amyloid Precursor Protein via Interaction with Adaptors GGA and PACS-1 J. Biol. Chem., November 9, 2007; 282(45): 32956 - 32964. [Abstract] [Full Text] [PDF]

				M. Khvotchev, I. Dulubova, J. Sun, H. Dai, J. Rizo, and T. C. Sudhof Dual Modes of Munc18-1/SNARE Interactions Are Coupled by Functionally Critical Binding to Syntaxin-1 N Terminus J. Neurosci., November 7, 2007; 27(45): 12147 - 12155. [Abstract] [Full Text] [PDF]

				S. M. Ostrowski, B. L. Wilkinson, T. E. Golde, and G. Landreth Statins Reduce Amyloid-beta Production through Inhibition of Protein Isoprenylation J. Biol. Chem., September 14, 2007; 282(37): 26832 - 26844. [Abstract] [Full Text] [PDF]

				C. A. F. von Arnim, R. Spoelgen, I. D. Peltan, M. Deng, S. Courchesne, M. Koker, T. Matsui, H. Kowa, S. F. Lichtenthaler, M. C. Irizarry, et al. GGA1 Acts as a Spatial Switch Altering Amyloid Precursor Protein Trafficking and Processing J. Neurosci., September 27, 2006; 26(39): 9913 - 9922. [Abstract] [Full Text] [PDF]

				K. S. Vetrivel and G. Thinakaran Amyloidogenic processing of {beta}-amyloid precursor protein in intracellular compartments Neurology, January 24, 2006; 66(1_suppl_1): S69 - S73. [Abstract] [Full Text] [PDF]

				O. M. Andersen, J. Reiche, V. Schmidt, M. Gotthardt, R. Spoelgen, J. Behlke, C. A. F. von Arnim, T. Breiderhoff, P. Jansen, X. Wu, et al. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein PNAS, September 20, 2005; 102(38): 13461 - 13466. [Abstract] [Full Text] [PDF]

				B. Angeletti, K. J. Waldron, K. B. Freeman, H. Bawagan, I. Hussain, C. C. J. Miller, K.-F. Lau, M. E. Tennant, C. Dennison, N. J. Robinson, et al. BACE1 Cytoplasmic Domain Interacts with the Copper Chaperone for Superoxide Dismutase-1 and Binds Copper J. Biol. Chem., May 6, 2005; 280(18): 17930 - 17937. [Abstract] [Full Text] [PDF]

				Q. Hu, L. Wang, Z. Yang, B. H. Cool, G. Zitnik, and G. M. Martin Endoproteolytic Cleavage of FE65 Converts the Adaptor Protein to a Potent Suppressor of the sAPP{alpha} Pathway in Primates J. Biol. Chem., April 1, 2005; 280(13): 12548 - 12558. [Abstract] [Full Text] [PDF]