Type II transmembrane serine proteases as potential targets for cancer therapy

Murray, Andrew S.; Varela, Fausto A.; List, Karin

doi:10.1515/hsz-2016-0131

Cited by 41 publications

(32 citation statements)

References 113 publications

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“…h uman a irway t rypsin (HAT)-like protease/ d ifferentially e xpressed in s quamous cell c arcinoma (DESC), hepsin/TMPRSS ( t rans m embrane pr otea s e/ s erine), matriptase, and corin subgroups4. Many of these TTSPs have been reported to play important roles in health and disease67891011. For example, matriptase is critical for epithelial integrity and function12.…”

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confidence: 99%

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

Zhang

Yan

et al. 2017

Sci Rep

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Membrane-bound proteases are essential for epidermal integrity. Human airway trypsin-like protease 4 (HAT-L4) is a type II transmembrane serine protease. Currently, its biochemical property, cellular distribution and physiological function remain unknown. Here we examined HAT-L4 expression and function in vitro and in vivo. In Western analysis, HAT-L4 expressed in transfected CHO cells appeared as a 48-kDa protein. Flow cytometry confirmed HAT-L4 expression on the cell surface with the expected membrane topology. RT-PCR and immunostaining experiments indicated that HAT-L4 was expressed in epithelial cells and exocrine glands in tissues including skin, esophagus, trachea, tongue, eye, bladder, testis and uterus. In the skin, HAT-L4 expression was abundant in keratinocytes and sebaceous glands. We generated HAT-L4 knockout mice by disrupting the Tmprss11f gene encoding HAT-L4. HAT-L4 knockout mice were viable and fertile. No defects were found in HAT-L4 knockout mice in hair growth, wound healing, water repulsion and body temperature regulation. Compared with wild-type controls, HAT-L4-deficient newborn mice had greater body fluid loss and higher mortality in a trans-epidermal body fluid loss test. In metabolic studies, HAT-L4-deficient adult mice drank water more frequently than wild-type controls did. These results indicate that HAT-L4 is important in epidermal barrier function to prevent body fluid loss.

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confidence: 99%

The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss

Zhang

Yan

et al. 2017

Sci Rep

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“…Thus, stably transfected TMPRSS2-overexpressing clones from a variety of prostate cancer cell lines showed increased levels of activated matriptase, which formed a 120-kDa complex with HAI-1 and corresponded with reduced levels of latent matriptase (70 kDa) and free HAI-1. These data were further corroborated by the finding that orthotopic grafts of LNCaP cells overexpressing TMPRSS2 increased both active matriptase and metastases, and that this increase is dependent upon TMPRSS2 catalytic activity [15, 65]. High-throughput screens of combinatorial libraries also identified pro-HGF as a substrate and it was confirmed that exogenous pro-HGF activated by incubation with TMPRSS2 was sufficient to activate the c-Met receptor, expressed in DU145 prostate cancer cells.…”

Section: Tmprss2mentioning

confidence: 71%

“…The dysregulation of matriptase is implicated in numerous cancers and associated with poor outcomes. For example, matriptase is shown to be overexpressed in a wide range of epithelial tumors (carcinomas) including of the breast, ovary, uterus, prostate, colon, cervix, and skin [1, 7, 15-17]. On the other hand some groups have described downregulation of matriptase mRNA in gastric and colorectal carcinomas [18, 19].…”

Section: Matriptasementioning

confidence: 99%

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

2016

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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.

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“…The structure of chymotrypsin in its co-crystal structure with LCMI-II has a highly-conserved backbone and binding site in comparison to cancer-associated serine proteases (32). Specifically, the type II transmembrane serine proteases matriptase, hepsin, TMPRSS2, and TMPRSS4 have been found to be overexpressed in many cancers, predominantly studied in prostate, breast, and ovarian cancers (33). Binding to these transmembrane proteins has the potential to trigger endocytosis and internalization of peptide-dye and peptide-drug conjugates that lead to payload delivery.…”

Section: Discussionmentioning

confidence: 99%