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

J. Biol. Chem., Vol. 282, Issue 42, 30509-30517, October 19, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/42/30509    most recent M702535200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marron, M. B. Articles by Brindle, N. P. J. Search for Related Content PubMed PubMed Citation Articles by Marron, M. B. Articles by Brindle, N. P. J. Social Bookmarking                      What's this?

Regulated Proteolytic Processing of Tie1 Modulates Ligand Responsiveness of the Receptor-tyrosine Kinase Tie2^*

Marie B. Marron¹², Harprit Singh¹, Tariq A. Tahir, Jais Kavumkal, Hak-Zoo Kim, Gou Young Koh, and Nicholas P. J. Brindle³

From the Department of Cardiovascular Sciences, University of Leicester, Robert Kilpatrick Clinical Sciences Bld., P. O. Box 65, Leicester, LE2 7LX United Kingdom and Biomedical Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1, Guseong-dong, Daejeon 305-701, Korea

Regulated ectodomain shedding followed by intramembrane proteolysis has recently been recognized as important in cell signaling and for degradation of several type I transmembrane proteins. The receptor-tyrosine kinase Tie1 is known to undergo ectodomain cleavage generating a membrane-tethered endodomain. Here we show Tie1 is a substrate for regulated intramembrane proteolysis. After Tie1 ectodomain cleavage the newly formed 45-kDa endodomain undergoes additional proteolytic processing mediated by -secretase to generate an amino-terminal-truncated 42-kDa fragment that is subsequently degraded by proteasomal activity. This sequential processing occurs constitutively and is stimulated by phorbol ester and vascular endothelial growth factor. To assess the biological significance of regulated Tie1 processing, we analyzed its effects on angiopoietin signaling. Activation of ectodomain cleavage causes loss of phosphorylated Tie1 holoreceptor and generation of phosphorylated receptor fragments in the presence of cartilage oligomeric protein angiopoietin 1. A key function of -secretase is in preventing accumulation of these phosphorylated fragments. We also find that regulated Tie1 processing modulates ligand responsiveness of the Tie-1-associated receptor Tie2. Activation of Tie1 ectodomain cleavage increases cartilage oligomeric protein angiopoietin 1 activation of Tie2. This correlates with increased ability of Tie2 to bind ligand after shedding of the Tie1 extracellular domain. A similar enhancement of ligand activation of Tie2 is seen when Tie1 expression is suppressed by RNA interference. Together these data indicate that Tie1, via its extracellular domain, limits the ability of ligand to bind and activate Tie2. Furthermore the data suggest that regulated processing of Tie1 may be an important mechanism for controlling signaling by Tie2.

Received for publication, March 23, 2007 , and in revised form, August 29, 2007.

^* This work was supported by British Heart Foundation Grants PG//2000122, PG/03/094, and PG/05/028. 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.

¹ Both authors contributed equally to this work.

² Present address: Cardiovascular Research Unit, Section of Cardiovascular Science, School of Medicine and Biomedical Sciences, University of Sheffield, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK.

³ To whom correspondence should be addressed. Tel.: 44-116-252-5802; Fax: 44-116-252-3179; E-mail: npjb1{at}le.ac.uk.

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

This article has been cited by other articles:

				J. H. Tsai and W. M.F. Lee Tie2 in Tumor Endothelial Signaling and Survival: Implications for Antiangiogenic Therapy Mol. Cancer Res., March 1, 2009; 7(3): 300 - 310. [Abstract] [Full Text] [PDF]

				V. W.M. van Hinsbergh and P. Koolwijk Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead Cardiovasc Res, May 1, 2008; 78(2): 203 - 212. [Abstract] [Full Text] [PDF]