We previously reported that CS (chondroitin sulfate) GAG (glycosaminoglycan), expressed on MCSP (melanoma-specific CS proteoglycan), is important for regulating MT3-MMP [membrane-type 3 MMP (matrix metalloproteinase)]-mediated human melanoma invasion and gelatinolytic activity in vitro. In the present study, we sought to determine if CS can directly enhance MT3-MMP-mediated activation of pro-MMP-2. Co-immunoprecipitation studies suggest that MCSP forms a complex with MT3-MMP and MMP-2 on melanoma cell surface. When melanoma cells were treated with βDX (p-nitro-β-D-xylopyranoside) to inhibit coupling of CS on the core protein, both active form and proform of MMP-2 were no longer co-immunoprecipitated with either MCSP or MT3-MMP, suggesting a model in which CS directly binds to MMP-2 and presents the gelatinase to MT3-MMP to be activated. By using recombinant proteins, we determined that MT3-MMP directly activates pro-MMP-2 and that this activation requires the interaction of the C-terminal domain of pro-MMP-2 with MT3-MMP. Activation of pro-MMP-2 by suboptimal concentrations of MT3-MMP is also significantly enhanced in the presence of excess C4S (chondroitin 4-sulfate), whereas C6S (chondroitin 6-sulfate) or low-molecular-mass hyaluronan was ineffective. Affinity chromatography studies using CS isolated from aggrecan indicate that the catalytic domain of MT3-MMP and the C-terminal domain of MMP-2 directly bind to the GAG. Thus the direct binding of pro-MMP-2 with CS through the C-domain would present the catalytic domain of pro-MMP-2 to MT3-MMP, which facilitates the generation of the active form of MMP-2. These results suggest that C4S, which is expressed on tumour cell surface, can function to bind to pro-MMP-2 and facilitate its activation by MT3-MMP-expressing tumour cells to enhance invasion and metastasis.
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May 2007
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Research Article|
April 12 2007
Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A)
Joji Iida
;
Joji Iida
1
*Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, U.S.A.
†Cancer Center, University of Minnesota, Minneapolis, MN 55455, U.S.A.
1To whom correspondence should be addressed (email iidax002@tc.umn.edu).
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Krista L. Wilhelmson
;
Krista L. Wilhelmson
*Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Janet Ng
;
Janet Ng
*Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Peter Lee
;
Peter Lee
‡Department of Surgery, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Charlotte Morrison
;
Charlotte Morrison
§Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3
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Eric Tam
;
Eric Tam
§Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3
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Christopher M. Overall
;
Christopher M. Overall
§Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3
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James B. McCarthy
James B. McCarthy
*Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, U.S.A.
†Cancer Center, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Biochem J (2007) 403 (3): 553–563.
Article history
Received:
August 02 2006
Revision Received:
January 02 2007
Accepted:
January 12 2007
Accepted Manuscript online:
January 12 2007
Citation
Joji Iida, Krista L. Wilhelmson, Janet Ng, Peter Lee, Charlotte Morrison, Eric Tam, Christopher M. Overall, James B. McCarthy; Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A). Biochem J 1 May 2007; 403 (3): 553–563. doi: https://doi.org/10.1042/BJ20061176
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