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J. Biol. Chem. 285 (30): 23047-23055

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Low Density Lipoprotein Receptor-related Protein-1 (LRP1) Regulates Thrombospondin-2 (TSP2) Enhancement of Notch3 Signaling*Formula

He Meng{ddagger}1, Xiaojie Zhang{ddagger}1, Soo Jung Lee{ddagger}, Dudley K. Strickland§, Daniel A. Lawrence, , and Michael M. Wang{ddagger}||2

From the Departments of {ddagger}Neurology,
Cardiology, and
||Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-5622 and
the §Department of Surgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201

ABSTRACT Back to Top

Abstract: Intracellular trafficking of Notch and Notch ligands modulates signaling, suggesting that choreography of ligand and receptor translocation is essential for optimal Notch activity. Indeed, a major model for Notch signaling posits that Notch trans-endocytosis into the ligand-expressing (signal sending) cell is a key driving force for Notch signal transduction. The extracellular protein thrombospondin-2 (TSP2) enhances Notch signaling and binds to both Jagged1 and Notch3 ectodomains, potentially bridging two essential extracellular components of Notch signaling. We investigated the role of low density lipoprotein receptor-related protein-1 (LRP1), a TSP2 receptor, in the regulation of Notch3 signaling. TSP2 potentiation of Notch is blocked by the receptor-associated protein (an inhibitor of low density lipoprotein receptor-related protein function) and requires LRP1 expression in the signal-sending cell. TSP2 stimulates Notch3 endocytosis into wild type fibroblasts but not LRP1-deficient fibroblasts. Finally, recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain, a subunit that lacks known ligand binding function. Our data suggest that LRP1 and TSP2 stimulate Notch activity by driving trans-endocytosis of the Notch ectodomain into the signal-sending cell and demonstrate a novel, non-cell autonomous function of LRP1 in cell-cell signaling.

Key Words: Lipoprotein-like Receptor (LRP) • Notch Pathway • Notch Receptor • Receptor Endocytosis • Thrombospondin • Notch3

Received for publication May 13, 2010.

FOOTNOTES Back to Top

1 Both authors contributed equally to this work.

2 To whom correspondence should be addressed: 7629 Medical Science Bldg. II, Box 5622, 1137 Catherine St., Ann Arbor, MI 48109-5622. Tel.: 734-763-5453; Fax: 734-936-8813; E-mail: micwang{at}umich.edu.

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