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J. Biol. Chem., Vol. 278, Issue 30, 27820-27827, July 25, 2003

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Identification of Peptide Substrates for Human MMP-11 (Stromelysin-3) Using Phage Display^*

Weijun Pan , Marc Arnone , Marvin Kendall ¶, Robert H. Grafstrom ||, Steven P. Seitz **, Zelda R. Wasserman  and Charles F. Albright  

From the Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08534

The MMP-11 proteinase, also known as stromelysin-3, probably plays an important role in human cancer because MMP-11 is frequently overexpressed in human tumors and MMP-11 levels affect tumorogenesis in mice. Unlike other MMPs, however, human MMP-11 does not cleave extracellular matrix proteins, such as collagen, laminin, fibronectin, and elastin. To help identify physiologic MMP-11 substrates, a phage display library was used to find peptide substrates for MMP-11. One class of peptides containing 26 members had the consensus sequence A(A/Q)(N/A)(L/Y)(T/V/M/R)(R/K), where denotes the cleavage site. This consensus sequence was similar to that for other MMPs, which also cleave peptides containing Ala in position 3, Ala in position 1, and Leu/Tyr in position 1', but differed from most other MMP substrates in that proline was rarely found in position 3 and Asn was frequently found in position 1. A second class of peptides containing four members had the consensus sequence G(G/A)ELR. Although other MMPs also cleave peptides with these residues, other MMPs prefer proline at position 3 in this sequence. In vitro assays with MMP-11 and representative peptides from both classes yielded modest k_cat/K_m values relative to values found for other MMPs with their preferred peptide substrates. These reactions also showed that peptides with proline in position 3 were poor substrates for MMP-11. A structural basis for the lower k_cat/K_m values of human MMP-11, relative to other MMPs, and poor cleavage of position 3 proline substrates by MMP-11 is provided. Taken together, these findings explain why MMP-11 does not cleave most other MMP substrates and predict that MMP-11 has unique substrates that may contribute to human cancer.

Received for publication, April 29, 2003

^* 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.

Present address: Epitomics, Inc., 1015 Grandview Dr., South San Francisco, CA 94080.

Present address: GlaxoSmithKline-Molecular Oncology, 1250 S. Collegeville Rd., UP1450, Collegeville, PA 19426.

^¶ Present address: Rm. H3B-330, DuPont Hospital for Children, 1600 Rockland Rd., Wilmington, DE 19899.

^|| Present address: Bristol-Myers Squibb Pharmaceutical Research Institute, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534.

^** Present address: Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 & Province Line Road, Lawrenceville, NJ 08543.

Present address: Incyte Pharmaceuticals, Stine Haskell Research Center, 1090 Elkton Rd., 115-36, Newark, DE 19711.

To whom correspondence should be addressed. Tel.: 302-283-7919; Fax: 302-283-7846; E-mail: cAlbright{at}incyte.com.

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