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Originally published In Press as doi:10.1074/jbc.M205317200 on July 8, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35671-35681, September 20, 2002
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Decorin Binds to a Narrow Region of the Epidermal Growth Factor (EGF) Receptor, Partially Overlapping but Distinct from the EGF-binding Epitope*

Manoranjan SantraDagger , Charles C. ReedDagger , and Renato V. IozzoDagger §

From the Dagger  Department of Pathology, Anatomy and Cell Biology, Room 249 Jefferson Alumni Hall and the § Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Decorin, a small leucine-rich proteoglycan, is a key regulator of tumor growth by acting as an antagonist of the epidermal growth factor receptor (EGFR) tyrosine kinase. To search for cell surface receptors interacting with decorin, we generated a decorin/alkaline phosphatase chimeric protein and used it to screen a cDNA library by expression cloning. We identified two strongly reactive clones that encoded either the full-length EGFR or its ectodomain. A physiologically relevant interaction between decorin and EGFR was confirmed in the yeast two-hybrid system and further validated by experiments using EGF/EGFR interaction and transient cell transfection assays. Using a panel of deletion mutants, decorin binding was mapped to a narrow region of the EGFR within its ligand-binding L2 domain. Moreover, the central leucine-rich repeat 6 of decorin was required for interaction with the EGFR. Site-directed mutagenesis of the EGFR L2 domain showed that a cluster of residues, His394-Ile402, was essential for both decorin and EGF binding. In contrast, K465, previously shown to be cross-linked to epidermal growth factor (EGF), was required for EGF but not for decorin binding. Thus, decorin binds to a discrete region of the EGFR, partially overlapping with but distinct from the EGF-binding domain. These findings could lead to the generation of protein mimetics capable of suppressing EGFR function.

* This work was supported by Grants RO1 CA39481 and RO1 CA47282 from the National Institutes of Health and by Grants DAMD17-00-1-0663 and DAMD17-00-1-0425 from the Department of the Army (to R.V.I.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Pathology, Anatomy and Cell Biology, Rm. 249 Jefferson Alumni Hall, Thomas Jefferson University, 1020 Locust St., Philadelphia, Pennsylvania 19107. E-mail: iozzo@lac.jci.tju.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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