Trends in Cell Biology
ReviewProteolytic networks in cancer
Section snippets
Proteolytic networks in cancer
Proteases, once thought of as little more than cellular garbage disposals or extracellular matrix (ECM) degraders, are one of the largest groups of enzymes in the human genome. There are 570 known human proteases [1], coupled with a smaller group of endogenous protease inhibitors that tightly regulate their activity. While proteases mediate both terminal protein degradation and ECM remodeling, recent findings have revealed their functions in tumors to be significantly more complex and varied.
Interactions of proteases within smaller, interconnected cascades
Individual proteases, with their broad range of targets, multitude of activation mechanisms and proposed impact on tumor progression and metastasis, cannot be fully understood without placing them in the proper context of upstream and downstream proteases serving as activators or substrates. Proteases are synthesized as inactive (or marginally active) zymogens and require cleavage, usually by other proteases, for activation. Much like the well-studied kinase cascades that control cellular
Fitting nodes into cascades: who's on top?
The interaction of caspases in a cascade leading to cell death has been established for some time and is not discussed further here (for a more extensive review of caspases, see [3]). Even though some proteases with pro-tumor functions can enhance the caspase cascade, the overall cascade is independent of the tumor-promoting interactions described above.
The major tumor-promoting roles ascribed to proteases in the tumor microenvironment usually include migration, invasion, angiogenesis,
Viewing proteolytic interactions in networks provides insight into in vivo results
Given the difficulty in finding a consistent entry point into a unified cascade, an alternative is to unite the smaller cascades discussed earlier. This provides a more accurate view of proteolytic interactions in the form of a network of small, interconnected proteolytic cascades (Figure 1). This perspective allows for constant modulation of proteolytic activity by any number of proteases, with up- or downregulation of the activity of one protease potentially affecting the overall activity of
Conclusions
Our understanding of the proteolytic network in the tumor microenvironment is expanding rapidly as the result of an increased interest in protease biology and new techniques that allow for comprehensive analysis of protease activity in physiologically relevant conditions. Much like the well established kinase signaling networks, proteolytic networks consist of multiple points of entry/activation, several key nodes through which a majority of signals pass, and inhibitors/deactivators that can
Acknowledgments
We thank members of the Joyce laboratory for discussion on this topic, and Dr Lisa Sevenich for critical review of the manuscript. Research in the Joyce laboratory is supported by the National Cancer Institute, the Breast Cancer Research Foundation and the Geoffrey Beene Foundation. S.M. was supported by a Ruth Kirschstein National Research Service Award from the NIH.
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