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Review
. 2011 Apr;21(4):228-37.
doi: 10.1016/j.tcb.2010.12.002. Epub 2011 Jan 12.

Proteolytic networks in cancer

Steven D Mason  1 , Johanna A Joyce
Affiliations
Review

Proteolytic networks in cancer

Steven D Mason et al. Trends Cell Biol. 2011 Apr.

Abstract

Proteases are important for multiple processes during malignant progression, including tumor angiogenesis, invasion and metastasis. Recent evidence reveals that tumor-promoting proteases function as part of an extensive multidirectional network of proteolytic interactions, in contrast to the unidirectional caspase cascade. These networks involve different constituents of the tumor microenvironment and key proteases, such as cathepsin B, urokinase-type plasminogen activator and several matrix metalloproteinases, occupy central nodes for amplifying proteolytic signals passing through the network. The proteolytic network interacts with other important signaling pathways in tumor biology, involving chemokines, cytokines, and kinases. Viewing these proteolytic interactions as a system of activating and inhibiting reactions provides insight into tumor biology and reveals relevant pharmaceutical targets. This review examines recent advances in understanding proteases in cancer and summarizes how the network of activity is co-opted to promote tumor progression.

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Figures

Figure 1
Figure 1
Different interactions within a proteolytic network. Visualizing proteolytic interactions as a network of coordinated cascades reveals that the network has multiple entry points, interactions are multidirectional, and signals can be amplified in many directions. Examining protease-protease interactions specifically shows that similar to the cascade view, several proteases occupy nodes in the network and function as key regulators of proteolytic activity. Additionally, interactions involve proteases of different families and can proceed in multiple different pathways, allowing for some proteases to compensate for the absence of others. References for proteolytic interactions not described in the main text: cathepsin D activates cathepsin L [18], cathepsin L activates cathepsin Z [90], cathepsin B activates cathepsin D, MMP2, and MMP3 [18, 75], tissue-type plasminogen activator (tPA) activates cathepsin B and plasmin [91], MMP14 can activate MMP2 [92], MMP2, MMP14, and plasmin can activate MMP13 [93], MMP14 activates MMP8 [94], MMP26 can activate KLK4 [26], and furin activates MMP11 and MMP14 [31].
Figure 2
Figure 2
Mechanisms of proteolytic regulation within the network. (a) Endogenous protein inhibitors can regulate proteolytic activity at multiple points in the network, allowing for tight regulation (or deregulation, if inhibitor expression is downregulated) of proteolytic activity. (b) Several proteases have been shown to degrade endogenous inhibitors, giving them the ability to increase the activity of other proteases indirectly. These interactions add further complexity to the network, and demonstrate how proteolytic signals can flow in multiple directions through different mechanisms. References for proteolytic interactions not described in the main text: cathepsin B can inactivate some serpins and TIMPs [95, 96], serpinB13/hurpin and serpinB3/SCCA1 inhibit cathepsin L [97, 98], cathepsin L inactivates serpinA1 [99], and several MMPs can inactivate a variety of serpins [29].
Figure 2
Figure 2
Mechanisms of proteolytic regulation within the network. (a) Endogenous protein inhibitors can regulate proteolytic activity at multiple points in the network, allowing for tight regulation (or deregulation, if inhibitor expression is downregulated) of proteolytic activity. (b) Several proteases have been shown to degrade endogenous inhibitors, giving them the ability to increase the activity of other proteases indirectly. These interactions add further complexity to the network, and demonstrate how proteolytic signals can flow in multiple directions through different mechanisms. References for proteolytic interactions not described in the main text: cathepsin B can inactivate some serpins and TIMPs [95, 96], serpinB13/hurpin and serpinB3/SCCA1 inhibit cathepsin L [97, 98], cathepsin L inactivates serpinA1 [99], and several MMPs can inactivate a variety of serpins [29].
Figure 3
Figure 3
Interactions between the proteolytic network and other pathways In addition to interactions with other proteases and endogenous inhibitors, proteases can modulate the activity of kinase signaling networks, cell surface receptors, and signaling molecules such as chemokines, cytokines, and growth factors. Depending on the protease and target protein, these can take the form of activating or degrading cleavages, allowing the proteolytic network to control the flow of signals in tumor cells as well as between tumor cells and the reactive stroma. Interactions are often bidirectional, as kinases also regulate many proteases via phosphorylation, and signaling molecules can indirectly (via signal transduction pathways) upregulate proteases in response to changes in the tumor microenvironment.
Figure I
Figure I. Proteolytic contributions from cells in the tumor microenvironment
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