Cell surface chondroitin sulfate glycosaminoglycan in melanoma: Role in the activation of pro-MMP-2 (pro-gelatinase A)

Joji Iida, Krista L. Wilhelmson, Janet Ng, Peter Lee, Charlotte Morrison, Eric Tam, Christopher M. Overall, James B. McCarthy

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)553-563
Number of pages11
JournalBiochemical Journal
Issue number3
StatePublished - May 1 2007


  • Chondroitin sulfate
  • Matrix metalloproteinase (MMP)
  • Membrane-type 3 MMP (MT3-MMP)
  • Proteoglycan
  • Sulfation
  • Tissue inhibitor of metalloproteinases-2 (TIMP-2)


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