Role of TMPRSS4 during cancer progression.

Proteases play important roles in the development and homeostasis of an organism. These versatile proteins participate in a variety of biological processes. In addition to these functions, the importance of proteases as a key player in cancer progression has been increasingly recognized. Proteolysis by dysregulated proteases is one of the hallmarks of cancer progression. In many cancers, a variety of functions have been uncovered for the type II transmembrane serine proteases (TTSPs), which are recently discovered members of the family of cell-surface associated proteases. In this review, we describe the characteristics of TTSPs and their role in many human cancers. Among the many TTSPs, we discuss TMPRSS4/MT-SP2 in the greatest detail. TMPRSS4 is upregulated in prostate, colon and gastric cancers, and was recently shown to promote tumor growth, invasion, metastasis and the epithelial-mesenchymal transition (EMT). Currently, efforts are being made to understand the pathways through which TMPRSS4 activates the EMT. Recent studies indicate that the EMT induced by TMPRSS4 involves activation of extracellular signal regulated kinase (ERK) 1/2 and mitogen-activated protein kinase (MAPK). The target molecule for TMPRSS4 that initiates the EMT stimulatory pathway is still not defined. Regulation of the EMT by proteases such as TMPRSS4 may provide novel therapeutic targets for a cancer metastasis inhibitor.