Redefining Metalloproteases Specificity through Network Proteolysis

Orit Kollet, Alakesh Das, Nikos Karamanos, Ulrich auf dem Keller, Irit Sagi*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Proteolytic processes on cell-surfaces and extracellular matrix (ECM) sustain cell-behavior and tissue integrity in health and disease. Matrix metalloproteases (MMPs) and a disintegrin and metalloproteinases (ADAMs) remodel cell microenvironments through irreversible proteolysis of ECM proteins and cell-surface bioactive molecules. Pan-MMP inhibitors in inflammation and cancer clinical trials have encountered challenges due to MMPs promiscuous activities. Systems-biology advances revealed that MMPs initiate multi-factorial proteolytic cascades, creating new substrates, activating, or suppressing other MMPs, and generating signaling molecules. This review highlights the intricate network that underscores MMPs role beyond individual substrate-enzyme activities. Gaining insight into MMP function and tissue specificity is crucial for developing effective drug discovery strategies and novel therapeutics. This requires considering the dynamic cellular processes and consequences of network-proteolysis.
Original languageEnglish
JournalTrends in Molecular Medicine
Volume30
Issue number2
Pages (from-to)147-163
ISSN1471-4914
DOIs
Publication statusPublished - 2024

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