Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase

Vladislav S. Golubkov, Piotr Cieplak, Alexei V. Chekanov, Boris I. Ratnikov, Alexander E. Aleshin, Natalya V. Golubkova, Tatiana I. Postnova, Ilian A. Radichev, Dmitri V. Rozanov, Wenhong Zhu, Khatereh Motamedchaboki, Alex Y. Strongin

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The functional activity of invasion-promoting membrane type 1 matrix metalloproteinase (MT1-MMP) is elevated in cancer. This elevated activity promotes cancer cell migration, invasion, and metastasis. MT1-MMP is synthesized as a zymogen, the latency of which is maintained by its prodomain. Excision by furin was considered sufficient for the prodomain release and MT1-MMP activation. We determined, however, that the full-length intact prodomain released by furin alone is a potent autoinhibitor of MT1-MMP. Additional MMP cleavages within the prodomain sequence are required to release the MT1-MMP enzyme activity. Using mutagenesis of the prodomain sequence and mass spectrometry analysis of the prodomain fragments, we demonstrated that the intradomain cleavage of the PGD↓L50 site initiates the MT1-MMP activation, whereas the 108RRKR111↓Y112 cleavage by furin completes the removal and the degradation of the autoinhibitory prodomain and the liberation of the functional activity of the emerging enzyme of MT1-MMP.

Original languageEnglish (US)
Pages (from-to)27726-27736
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number36
DOIs
StatePublished - Sep 3 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Golubkov, V. S., Cieplak, P., Chekanov, A. V., Ratnikov, B. I., Aleshin, A. E., Golubkova, N. V., Postnova, T. I., Radichev, I. A., Rozanov, D. V., Zhu, W., Motamedchaboki, K., & Strongin, A. Y. (2010). Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase. Journal of Biological Chemistry, 285(36), 27726-27736. https://doi.org/10.1074/jbc.M110.135442