Cell surface-anchored serine proteases in cancer progression and metastasis

Abstract

Over the last two decades, a novel subgroup of serine proteases, the cell surface-anchored serine proteases, has emerged as an important component of the human degradome, and several members have garnered significant attention for their roles in cancer progression and metastasis. A large body of literature describes that cell surface-anchored serine proteases are deregulated in cancer and that they contribute to both tumor formation and metastasis through diverse molecular mechanisms. The loss of precise regulation of cell surface-anchored serine protease expression and/or catalytic activity may be contributing to the etiology of several cancer types. There is therefore a strong impetus to understand the events that lead to deregulation at the gene and protein levels, how these precipitate in various stages of tumorigenesis, and whether targeting of selected proteases can lead to novel cancer intervention strategies. This review summarizes current knowledge about cell surface-anchored serine proteases and their role in cancer based on biochemical characterization, cell culture-based studies, expression studies, and in vivo experiments. Efforts to develop inhibitors to target cell surface-anchored serine proteases in cancer therapy will also be summarized.

Keywords: Cancer; Hepsin; Matriptase; Prostasin; TMPRSS2; TMPRSS3; TMPRSS4; Testisin; Type II transmembrane serine proteases.

Figure 1.. Overview of human membrane-anchored serine proteases and cognate inhibitors

A) The type II transmembrane serine protease (TTSP) family members are attached to the membrane via a signal anchor (SA) located close to the N terminus. TTSPs are phylogenetically divided into four subfamilies: 1) matriptase, 2) hepsin/transmembrane protease, serine (TMPRSS), 3) human airway trypsin-like (HAT)/differentially expressed in squamous cell carcinoma gene (DESC), 4) corin. Asterisks indicate proteases included in this review. B) Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors. They have two extracellular Kunitz-type serine proteinase inhibitor domains (KD1 and KD2), a single-pass transmembrane domain near the carboxyl terminus, and a short intracytoplasmic domain. Two major splicing variants (isoforms a and b) of HAI-2 are known where the b isoform lacks KD1. HAI-2a is the predominant form in humans. C) Prostasin and testisin are composed of a single protease domain linked to a glycosylphosphatidylinositol (GPI) anchor that is added posttranslationally to the C terminus and attaches the proteases to the outer leaflet of the plasma membrane. Domains: SA=signal anchor, LDLA=low-density lipoprotein receptor class A, SRCR=group A scavenger receptor cysteine-rich, SP=serine protease, SEA= sea urchin sperm protein, enteropeptidase, agrin, CUB=Cls/Clr, urchin embryonic growth factor, bone morphogenetic protein-1, MAM= meprin, A5 antigen, receptor protein phosphatase μ. TM=transmembrane, KD1=Kunitz-type serine proteinase inhibitor domain 1, KD2=Kunitz-type serine proteinase inhibitor domain 2, PKD=polycystic kidney disease (PKD)-like, MANEC=motif at N terminus with eight cysteines, GPI=glycosylphosphatidylinositol anchor.

Figure 2.. Roles of cell-surface anchored serine proteases in cancer development and progression.

Cell-surface anchored serine proteases are involved in the development/initiation of primary tumors (determined through genetic mouse models), progression of primary tumors (determined through apoptosis/proliferation assays cell culture assays and/or xenograft models), cancer cell migration/invasion (determined through invasion assays in vitro) and formation of metastatic lesions (determined through metastasis development in genetic mouse models and/or xenograft models). Upward-facing arrows indicate proteases that are positively associated with tumor development/progression (pro-oncogenic) and downward-facing arrows indicate proteases negatively associated with tumor development/progression (tumor suppressive).