Prointegrin maturation follows rapid trafficking and processing of MT1-MMP in furin-negative colon carcinoma LoVo cells

Elena I. Deryugina, Boris I. Ratnikov, Qing Yu, Peter C. Baciu, Dmitri V. Rozanov, Alex Y. Strongin

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Understanding the function of invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) is of paramount importance for understanding cancer biology. MT1-MMP is synthesized in cells as a latent zymogen that requires the cleavage of its prodomain to exert the proteolytic activity. The mature αv integrin subunit is also generated by endoproteolytic cleavage of the αv subunit precursor (pro-αv). Cleavage by furin is considered to be a principal event in the activation of both MT1-MMP and pro-αv. To elucidate the alternative activation pathway of MT1-MMP and pro-αv, we employed furin-negative LoVo cells, which co-express MT1-MMP with integrin α vβ3. In these cells the MT1-MMP proenzyme was rapidly trafficked to the plasma membrane via an unconventional Brefeldin A-resistant pathway and, then, autocatalytically processed on the cell surface. Next, the MT1-MMP activity converted the cell surface-associated pro-αv into the mature αv integrin, represented by the disulfide-bonded heavy and light chains, and promoted the formation of the functional integrin αvP3 heterodimer. These events stimulated cell motility in vitro, and malignant invasion and tumor growth in vivo. Our data suggest that in furin-negative colon carcinoma cells MT1-MMP is autocatalytically processed and the active protease then operates as a prointegrin convertase. Our findings argue strongly that the processing by furin is not a prerequisite for the activation of MT1-MMP.

Original languageEnglish (US)
Pages (from-to)627-641
Number of pages15
JournalTraffic
Volume5
Issue number8
DOIs
StatePublished - Aug 2004

Keywords

  • Angiogenesis
  • Extracellular matrix
  • Furin
  • Invasion
  • MT1-MMP
  • Migration
  • Proproteins

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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