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) [1], 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 [2, 3]. 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 [2, 4-6]. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling.

Hepatocyte growth factor activator inhibitors (HAI‐1 and HAI‐2): Emerging key players in epithelial integrity and cancer

“…Consequently, proteolysis has considerable influence on the outside‐in signaling required for cellular homeostasis, responses to injury and regeneration . Dysregulated proteolysis is observed in diseased tissues, including tumors, and sometimes, it is a causal factor of the disease …”

Ectopic expression of human airway trypsin‐like protease 4 in acute myeloid leukemia promotes cancer cell invasion and tumor growth

“…The mechanism underlying the ectopic HAT‐L4 expression in AML is unclear. Among TTSPs overexpressed in cancer, TMPRSS2 expression in prostate cancer is regulated by an androgen response element in the gene promotor . Moreover, gene translocations have been identified between the TMPRSS2 promotor and members of the E26 transformation‐specific transcription factor family, which disrupts normal androgen receptor signaling and activates tumor–promoting epigenetic programs .…”

“…In cancers, TTSP overexpression has been shown to enhance oncogenic signaling and promote tumor progression . Most TTSP overexpression occurs in solid tumors.…”

Knockdown of TMPRSS3 inhibits cell proliferation, migration/invasion and induces apoptosis of glioma cells

“…Further studies showed that TMPRSS3 knockdown suppressed cell proliferation, migration, invasion, and induced cell apoptosis of glioma cell lines. Proteases have been increasingly recognized as important factors in the pathophysiology of tumors, which is because they can promote tumor growth since they have the capacity to break down the surrounding extracellular matrix components . Therefore, they can pave the way for spreading, and they also release and activate growth and angiogenic factors .…”