The role of type II transmembrane serine protease-mediated signaling in cancer

Abstract

Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix (ECM) protein-degrading enzymes which allowed cancer cells to breach the basement membrane and invade surrounding tissue. However, recently, there has been a shift in the view of cell surface proteases, including serine proteases, as proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. Of the 176 human serine proteases currently identified, a subset of 17, known as type II transmembrane serine proteases (TTSPs). Many have been shown to be relevant to cancer progression since they were first identified as a family around the turn of the century. To this end, altered expression of TTSPs appeared as a trademark of several tumor types. However, the substrates and underlying signaling pathways remained unclear. Localization of these proteins to the cell surface places them in the unique position to mediate signal transduction between the cell and its surrounding environment. Many of the TTSPs have already been shown to play key roles in processes such as postnatal development, tissue homeostasis, and tumor progression, which share overlapping molecular mechanisms. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling.

Keywords: TMPRSS2; TMPRSS4; cancer; hepsin; matriptase; small molecule inhibitors; type II transmembrane serine proteases.

Figure 1. Proposed pro-oncogenic signaling pathways for TTSPs, matriptase, hepsin, TMPRSS2, and TMPRSS4

The HGF/c-Met cell survival pathway is activated by matriptase, hepsin, and TMPRSS2. Similarly, matriptase and hepsin are able to cleave and activate pro-MSP-1, and pro-uPA, and activate RON, and bind to uPAR receptors, respectively. The PAR-2/NFκB pathway is activated by matriptase and TMPRSS2. TMPRSS4 is associated with signaling through the ITG-α5 pathway. Other substrates of matriptase include CDCP1/TRASK/SIMA135 (not shown) and PDGF-D (not shown) and prostasin. Matriptase was also shown to be a substrate of both hepsin and TMPRSS2. HAI-1 and HAI-2 are cell-surface endogenous inhibitors of both matriptase and hepsin