Allosteric antibody inhibition of human hepsin protease

Koschubs, Tobias; Dengl, Stefan; Dürr, Harald; Kaluza, Klaus; Georges, Guy; Hartl, C.; Jennewein, Stefan; Lanzendörfer, Martin; Auer, Johannes; Stern, Alvin S.; Huang, Kuo‐Sen; Packman, Kathryn; Gubler, Ueli; Kostrewa, Dirk; Ries, Stefan; Hansen, Silke; Kohnert, Ulrich; Cramer, Patrick; Mundigl, Olaf

doi:10.1042/bj20111317

Cited by 30 publications

(29 citation statements)

References 57 publications

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“…Interestingly, a specific antibody acting as an allosteric inhibitor of catalytic activity that binds at the periphery of the substrate binding site of HGFA has been reported . This allosteric inhibition mechanism may have implications for the development of innovative strategies to regulate HGF/SF‐activating TTSPs possibly involved in cancer progression …”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

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The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the proto-oncogene MET), which are necessary for cellular migration, survival, growth and triggering stem cells for accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development and integrity, as well as tumorigenesis and progression of transformed epithelial cells.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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

Kataoka

Kawaguchi

Fukushima

et al. 2018

Pathology International

129

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“…In addition to Kunitz domain-1, development of several antibodies specifically inhibiting Hepsin have been reported [13, 29, 30]. While Hepsin antibodies are likely to be useful for prostate cancer imaging, the therapeutic use of these antibodies for tumor eradication may be somewhat limited due to the prominent expression of endogenous Hepsin in hepatocytes [31].…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

et al. 2014

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The development of effective therapies inhibiting prostate cancer progression and metastasis may substantially impact prostate cancer mortality and potentially reduce the rates of invasive treatments by enhancing the safety of active surveillance strategies. Hepsin (HPN) is a cell surface serine protease amplified in a subset of human sarcomas (7.2%), as well as in ovarian (10%), lung adeno (5.4%), lung squamous cell (4.5%), adenoid cystic (5%), breast (2.6%), uterine (1.7%) and colon (1.4%) carcinomas. While HPN is not amplified in prostate cancer, it is one of the most prominently overexpressed genes in the majority of human prostate tumors and genetic experiments in mice indicate that Hepsin promotes prostate cancer metastasis, particularly metastasis to the bone marrow. We report here the development, analysis and animal trial of the small-molecule Hepsin inhibitor HepIn-13. Long-term exposure to HepIn-13 inhibited bone, liver and lung metastasis in a murine model of metastatic prostate cancer. These findings indicate that inhibition of Hepsin with small-molecule compounds could provide an effective tool for attenuation of prostate cancer progression and metastasis.

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“…In addition to these inhibitors, studies using antibodies targeting hepsin have also been reported. The monoclonal, humanized, allosteric antibody, hH35, inhibits hepsin enzymatic activity at nanomolar concentrations [127]. Fab25, found by screening a Fab phage display library, is another allosteric inhibitor [78], although effects in either cell-or animal-based systems remain unexplored.…”

Section: Ttsps As Novel Therapeutic Targets In Cancermentioning

confidence: 99%

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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Allosteric antibody inhibition of human hepsin protease

Cited by 30 publications

References 57 publications

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

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

Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis

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

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