Hepatocyte growth factor: a multifunctional cytokine

Boros, Péter; Miller, Crystal

doi:10.1016/s0140-6736(95)90279-1

Cited by 304 publications

(195 citation statements)

References 21 publications

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“…This further supports our hypothesis that hepsin affects cell sizes through the HGF/c-Met pathway. The possibility, therefore, exists that the increase in the hepatocyte and stellate cell size could be partially attributed to the effect of hepsin loss in other organs that also coexpress HGF, 31 but the significance of such a possibility is unknown. A more-detailed characterization of the liver phenotypes of mice with a liver-specific loss of hepsin, HGF, and c-Met 32 will help address this issue and rule out the possibility that the current liver phenotypes are caused by the systemic effect of the general disruption of hepsin expression.…”

Section: Discussionmentioning

confidence: 99%

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Hsu

Huang

et al. 2012

Hepatology

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The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin 2/2 ) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin 2/2 mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin 2/2 mice. Treatment of hepsin 2/2 mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin 2/2 mice. Conclusion: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver. (HEPATOLOGY 2012;56:1913-1923 T ype II transmembrane serine proteases (TTSPs) have important physiological functions and pathological implications in iron metabolism, 1 blood pressure regulation, and metastasis of cancers. 2 More than 20 TTSPs exist and they are divided into four subfamilies. Among these families, the hepsin/ enteropeptidase subfamily is recognized structurally by a scavenger receptor cysteine-rich domain linked to a serine protease domain contained within an extracellular stem region. Although hepsin may be involved in the progression of several human cancers, 3 its physiological function has not yet been fully characterized. Hepsin is predominantly expressed in the liver. 4 Antisenseoligonucleotide blockade of hepsin affects cell growth and enlarges and flattens hepatoma cells. 5 Several in vitro studies have identified substrates for hepsin, including coagulation factor VII, 6 prohepatocyte growth factor (pro-HGF), 7 and prourokinase-type plasminogen activator. 8 In addition, hepsin colocalizes with desmoplakin at the sites of desmosomal junctions. 9

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Section: Discussionmentioning

confidence: 99%

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Hsu

Huang

et al. 2012

Hepatology

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“…Hepatocyte growth factor (HGF)/scatter factor, which was first isolated as a liver-regenerating factor from the plasma of patients with fulminant hepatitis and rat platelets, is now known as a multifunctional factor regulating cell growth, motility, and migration [1][2][3][4][5]. It is also known to regulate tumor invasion [6], morphogenesis [3,7], and organ regeneration [3,8].…”

Section: Introductionmentioning

confidence: 99%

HGF Activates Signal Transduction from EPO Receptor on Human Cord Blood CD34 ⁺ /CD45 ⁺ Cells

et al. 1999

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“…Upon binding to its cognate tyrosine kinase receptor, c-Met, HGF activates multiple signaling pathways (4,5), including phosphatidylinositol 3-kinase-Akt, Ras-Mek-Erk, and the Stat3 pathways, and thereby modulates a variety of cell processes, including mitogenesis, motogenesis, morphogenesis, and antiapoptosis/prosurvival in a number of cell types (1)(2)(3)(4)(5)(6)(7). In vivo, HGF has been shown to protect against acute and chronic injury in multiple organ systems, including liver (8), lung (9), intestine (10), and kidney (11).…”

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confidence: 99%

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

Gong

Rifai

et al. 2008

Journal of Biological Chemistry

108

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Activation of NF B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3␤ suppresses NF B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3␤ consensus motif and could be directly phosphorylated by GSK3␤ both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3␤. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3␤. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3␤. HGF substantially intercepted this interaction by inactivating GSK3␤. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF B-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF B activation was consistently mimicked by a selective GSK3␤ inhibitor or GSK3␤ knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3␤. Collectively, our findings suggest that HGF has a potent suppressive effect on NF B activation, which is mediated by GSK3␤, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.

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Hepatocyte growth factor: a multifunctional cytokine

Cited by 304 publications

References 21 publications

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

HGF Activates Signal Transduction from EPO Receptor on Human Cord Blood CD34 ⁺ /CD45 ⁺ Cells

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

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Hepatocyte growth factor: a multifunctional cytokine

Cited by 304 publications

References 21 publications

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

HGF Activates Signal Transduction from EPO Receptor on Human Cord Blood CD34 + /CD45 + Cells

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

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HGF Activates Signal Transduction from EPO Receptor on Human Cord Blood CD34 ⁺ /CD45 ⁺ Cells