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J. Biol. Chem., Vol. 279, Issue 42, 43503-43513, October 15, 2004

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Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by ₂₁ Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen^*

Diane Baronas-Lowell, Janelle L. Lauer-Fields, Jeffrey A. Borgia, Gian Franco Sferrazza, Mohammad Al-Ghoul, Dmitriy Minond, and Gregg B. Fields

From the Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431-0991

Tumor cell binding to components of the basement membrane is well known to trigger intracellular signaling pathways. Signaling ultimately results in the modulation of gene expression, facilitating metastasis. Type IV collagen is the major structural component of the basement membrane and is known to be a polyvalent ligand, possessing sequences bound by the ₁₁, ₂₁, and ₃₁ integrins, as well as cell surface proteoglycan receptors, such as CD44/chondroitin sulfate proteoglycan (CSPG). The role of ₂₁ integrin and CD44/CSPG receptor binding on human melanoma cell activation has been evaluated herein using triple-helical peptide ligands incorporating the 1(IV)382–393 and 1(IV)1263–1277 sequences, respectively. Gene expression and protein production of matrix metalloproteinases-1 (MMP-1), -2, -3, -13, and -14 were modulated with the ₂₁-specific sequence, whereas the CD44-specific sequence yielded significant stimulation of MMP-8 and lower levels of modulation of MMP-1, -2, -13, and -14. Analysis of enzyme activity confirmed different melanoma cell proteolytic potentials based on engagement of either the ₂₁ integrin or CD44/CSPG. These results are indicative of specific activation events that tumor cells undergo upon binding to select regions of basement membrane collagen. Based on the present study, triple-helical peptide ligands provide a general approach for monitoring the regulation of proteolysis in cellular systems.

Received for publication, May 28, 2004 , and in revised form, July 12, 2004.

^* This work was supported by National Institutes of Health Grants CA77402 and CA98799 (to G. B. F.) and Florida Atlantic University Center of Excellence in Biomedical and Marine Biotechnology Grant P200409. 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: Dept. of Biochemistry, Rush University Medical College, 536-D Cohn Research Bldg., 1735 West Harrison St., Chicago, IL 60612. E-mail: Jeffrey_Borgia{at}rush.edu.

To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Rd., Boca Raton, FL 33431-0991. Tel.: 561-297-2093; Fax: 561-297-2759; E-mail: fieldsg{at}fau.edu.

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