Abstract
Matrix metalloproteinases (MMPs) have been studied in the context of cancer due to their ability to increase cell invasion, and were initially thought to facilitate metastasis solely through the degradation of the extracellular matrix (ECM). MMPs have also been investigated in the context of their ECM remodeling activity in several acute and chronic inflammatory diseases. However, after several MMP inhibitors failed in phase III clinical trials, a global reassessment of their biological functions was undertaken, which has revealed multiple unanticipated functions including the processing of chemokines, cytokines, and cell surface receptors. Despite what their name suggests, the matrix aspect of MMPs could contribute to a lesser part of their physiological functions in inflammatory diseases, as originally anticipated. Here, we present examples of MMP substrates implicated in cell signaling, independent of their ECM functions, and discuss the impact for the use of MMP inhibitors.
Highlights
Matrix metalloproteinases (MMPs) have been associated with multiple inflammatory diseases [1,2,3], but the initial hypothesis that their proteolytic functions were solely linked to extracellular matrix (ECM) remodeling is outdated and needs to be extended to include additional substrates such as chemokines, cytokines, and cell surface receptors [4,5,6,7,8,9]
Cell surface receptors act as gatekeepers of cell signaling networks, as they provide the integral component that allows extracellular messages to be converted to intracellular signals
This occurs at a unique peptide sequence between 41R↓S42 (Table 1), liberating an N-terminal fragment that functionally interacts with the C-terminal region of the exodomain on PAR1 and triggers signal transduction from the G-protein coupled receptors (GPCRs) (Figure 1)
Summary
Matrix metalloproteinases (MMPs) have been associated with multiple inflammatory diseases [1,2,3], but the initial hypothesis that their proteolytic functions were solely linked to extracellular matrix (ECM) remodeling is outdated and needs to be extended to include additional substrates such as chemokines, cytokines, and cell surface receptors [4,5,6,7,8,9]. MMPs are multi-tasking proteins that play key roles in cellular interactions and signaling; similar to emojis in our messages and social media posts, MMPs are able to tune and modulate cellular communications. Both emojis and MMPs are often misunderstood. We describe examples of MMP substrates that are implicated in cell-to-cell communication and their physiological connection to inflammatory diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
