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Involvement of Disulfide Bond Formation in the Activation of Heparanase

¹ Antibiotics Laboratory and ² Biomolecular Characterization Team, Discovery Research Institute, RIKEN and ³ Graduate School of Science and Engineering, Saitama University, Saitama, Japan

Requests for reprints: Hiroyuki Osada, Antibiotics Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Phone: 81-48-467-9541; Fax: 81-48-462-4669; E-mail: hisyo{at}riken.jp.

Heparanase is overexpressed in many solid tumor cells and is capable of specifically cleaving heparan sulfate, and this activity is associated with the metastatic potential of tumor cells; however, the activation mechanism of heparanase has remained unknown. In this study, we investigated the link between disulfide bond formation and the activation of heparanase in human tumor cells. Mass spectrometry analysis of heparanase purified from a conditioned medium of human fibrosarcoma cells revealed two disulfide bonds, Cys¹²⁷-Cys¹⁷⁹ and Cys⁴³⁷-Cys⁵⁴², and one S-cysteinylation at the Cys²¹¹ residue. It was shown that, although the formation of the Cys¹²⁷-Cys¹⁷⁹ bond and S-cysteinylation at Cys²¹¹ have little effect on heparanase function, the disulfide bond between Cys⁴³⁷ and Cys⁵⁴² is necessary for the secretion and activation of heparanase. Thus, the present findings will provide a basis for the further refinement of heparanase structural studies and for the development of novel heparanase inhibitors. [Cancer Res 2007;67(16):7841–9]

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