Activation Mechanisms of the Urokinase-type Plasminogen Activator Promoter by Hepatocyte Growth Factor/Scatter Factor

Ried, Sabine; Jäger, Christoph; Jeffers, Michael; Woude, George F. Vande; Graeff, H.; Schmitt, Manfred; Lengyel, Ernst

doi:10.1074/jbc.274.23.16377

Cited by 84 publications

(65 citation statements)

References 54 publications

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“…Hepsin also activates the latent form of the invasive growth factor HGF (17,18), and both HGF and uPA have been implicated in prostate cancer growth and metastasis (45)(46)(47)(48). Moreover, by activating pro-HGF, hepsin may directly regulate the local levels of its substrate pro-uPA since HGF was shown to induce pro-uPA transcription and protein synthesis (49,50). Therefore, tumor cell surfaceexpressed hepsin could be central in orchestrating invasive pathways at the tumor/stroma interface.…”

Section: Discussionmentioning

confidence: 99%

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

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Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys 158 -Ile 159 (P 1 -P 1 ) peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (k cat /K m 4.8 ؋ 10 5 M ؊1 s ؊1 ) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 ؎ 1.9 nM uPA h ؊1 , which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.Hepsin is a type II transmembrane serine protease expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain, and a single scavenger receptor cysteinerich domain that packs tightly against the C-terminal protease domain (1). The physiologic function of hepsin remains unknown. Despite its expression in the very early stages of embryogenesis (2), hepsin-deficient mice were viable and developed normally (3, 4). The studies further showed that hepsin was not essential for liver regeneration and for coagulationrelated physiological functions (3, 4). However, hepsin has been implicated in ovarian cancer (5) and prostate cancer (6 -11), where several gene expression studies have identified it as one of the most highly induced genes. Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia but strongly increased in prostate carcinoma, particularly in advanced stages (8 -10). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades...

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Section: Discussionmentioning

confidence: 99%

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

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“…These proteases are critical in degrading the ECM and allowing migration of tumor cells through the basement membrane and the surrounding stroma [90]. Based on the multitude of activities and interactions during tumor progression, c-Met represents an important mediator of cell migration and metastasis and, hence, cMet-mediated signaling pathways are in the spotlight as potential targets for the development of anti-metastatic therapy [91].…”

Section: C-met and Hepatocyte Growth Factor/scatter Factor (Hgf/sf)mentioning

confidence: 99%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

210

160

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Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

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“…Recent evidence has further demonstrated that HGF can in turn effect u-PA expression. A number of cell lines have been shown to up-regulate u-PA in response to HGF in vitro [18][19][20][21][22][23][24][25][26] presumably through increased transcription following Map kinase/AP-1 activation down stream of MET [27]. CaP cell lines have been shown to express u-PA in vitro and u-PA over expression in Mat Ly Lu CaP cells was shown to enhance bone metastasis following intracardiac injection.…”

Section: Introductionmentioning

confidence: 99%

Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase‐type plasminogen activator (u‐PA)

et al. 2003

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BACKGROUND. Increased expression of the hepatocyte growth factor (HGF) receptor (MET) is associated with high-grade prostatic adenocarcinoma and metastasis. However, the mechanism through which MET signaling contributes to prostate cancer (CaP) metastasis remains unclear. METHODS. Human PC-3 CaP cells and in vivo selected, isogeneic variant cells of increasing metastatic potential (PC-3M, PC-3M-Pro4, and PC-3M-LN4) were used to investigate the effect of HGF on CaP cell growth, protease production, and invasion. Cell-free urokinase-type plasminogen activator (u-PA) expression and function following HGF treatment were analyzed by Western blot, ELISA, and casein/plasminogen zymography. In vitro invasion stimulated by HGF was measured using Matrigel-coated invasion chambers. RESULTS. Both mRNA and functional protein for MET were detected in each of the CaP cell lines. HGF treatment (0-40 ng/ml) weakly increase proliferation, however, HGF induced soluble u-PA protein and activity 3-fold in the metastatic variant cells. HGF significantly stimulated the invasion of highly metastatic PC-3M-LN4 cells through Matrigel and treatment with specific urokinase receptor inhibitors diminished the HGF-stimulated invasion in a dosedependent manner.CONCLUSIONS. These results demonstrate the biological significance of u-PA up-regulation in response to HGF in highly metastatic hormone refractory CaP cells.

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Activation Mechanisms of the Urokinase-type Plasminogen Activator Promoter by Hepatocyte Growth Factor/Scatter Factor

Cited by 84 publications

References 54 publications

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase‐type plasminogen activator (u‐PA)

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