TY - JOUR
T1 - Redefining Metalloproteases Specificity through Network Proteolysis
AU - Kollet, Orit
AU - Das, Alakesh
AU - Karamanos, Nikos
AU - Keller, Ulrich auf dem
AU - Sagi, Irit
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1016/j.molmed.2023.11.001
DO - 10.1016/j.molmed.2023.11.001
M3 - Journal article
C2 - 38036391
SN - 1471-4914
VL - 30
SP - 147
EP - 163
JO - Trends in Molecular Medicine
JF - Trends in Molecular Medicine
IS - 2
ER -