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