Metalloproteinases and cell fate: Notch just ADAMs anymore

Eric T. Sawey, Howard C. Crawford

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Notch signaling is involved both in development as well as in multiple cancers, including pancreatic cancer. Its activity has been implicated early in pancreatic disease, shown to be essential for a pre-cancerous transdifferentiation event known as acinar-toductal metaplasia (ADM). Recently, we have shown that matrix metalloproteinase-7 (MMP-7) is essential for ADM by activating the Notch pathway, challenging the notion that ADAM metalloproteinases are the sole enzymes responsible for initiating Notch activity. In ADM, ADAMs do not compensate for the absence of MMP-7 activity. We propose that during development and stem cell maintenance, Notch activation is highly regulated by the binding of Notch ligand to receptor and employs the ubiquitously-expressed ADAMs, whereas in a disease state, high levels of induced MMP-7 activity can lead to aberrant ligand-independent Notch activation. Therefore, if ADM or PDA is to be blocked by inhibiting Notch, treatment with ADAM-specific inhibitors alone will be inadequate. Other approaches for Notch inhibition, including by γ-secretase and broad-spectrum MMP inhibitors, will be discussed.

Original languageEnglish (US)
Pages (from-to)566-569
Number of pages4
JournalCell Cycle
Volume7
Issue number5
DOIs
StatePublished - Mar 1 2008

Keywords

  • ADAM-10
  • ADAM-17
  • Gamma secretase inhibitor
  • Jagged
  • MMP-7
  • Matrilysin
  • Metaplasia
  • Pancreatic cancer
  • Transdifferentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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