scholarly journals Hepatocyte Growth Factor-Dependent Antiviral Activity of Activated cdc42-Associated Kinase 1 Against Hepatitis B Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Hye Won Lee ◽  
Yongwook Choi ◽  
Ah Ram Lee ◽  
Cheol-Hee Yoon ◽  
Kyun-Hwan Kim ◽  
...  
Keyword(s):  
Life Cycle ◽  
Growth Factor ◽  
Antiviral Activity ◽  
Hepatocyte Growth Factor ◽  
Hbv Infection ◽  
Mitogen Activated Protein Kinase ◽  
Transcriptional Level ◽  
Enhancer Activity ◽  
Hbv Replication ◽  
Hepatocyte Growth

Activated cdc42-associated kinase 1 (ACK1) is a well-known non-receptor tyrosine kinase that regulates cell proliferation and growth through activation of cellular signaling pathways, including mitogen-activated protein kinase (MAPK). However, the anti-HBV activity of ACK1 has not been elucidated. This study aimed to investigate the role of ACK1 in the HBV life cycle and the mechanism underlying the anti-HBV activity of ACK1. To examine the antiviral activity of ACK1, we established HepG2-ACK1 cells stably overexpressing ACK1. The HBV life cycle, including HBeAg/HBsAg secretion, HBV DNA/transcription, and enhancer activity, was analyzed in HepG2 and HepG2-ACK1 cells with HBV replication-competent HBV 1.2mer (HBV 1.2). Finally, the anti-HBV activity of ACK1 was examined in an HBV infection system. ACK1 suppressed HBV gene expression and transcription in HepG2 and HepG2-ACK1 cells. Furthermore, ACK1 inhibited HBV replication by decreasing viral enhancer activity. ACK1 exhibited its anti-HBV activity via activation of Erk1/2, which consequently downregulated the expression of HNF4α binding to HBV enhancers. Furthermore, hepatocyte growth factor (HGF) induced ACK1 expression at an early stage. Finally, ACK1 mediated the antiviral effect of HGF in the HBV infection system. These results indicated that ACK1 induced by HGF inhibited HBV replication at the transcriptional level by activating the MAPK-HNF signaling pathway. Our findings suggest that ACK1 is a potentially novel upstream molecule of MAPK-mediated anti-HBV activity.

Differential regulation of hepatocyte growth factor/scatter factor by cell surface proteoglycans and free glycosaminoglycan chains

1999 ◽  
Vol 112 (12) ◽  
pp. 1999-2009 ◽  
Author(s):  
J.A. Deakin ◽  
M. Lyon
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Hepatocyte Growth Factor ◽  
Cell Motility ◽  
Heparan Sulphate ◽  
Mitogen Activated Protein Kinase ◽  
Dermatan Sulphate ◽  
Mitogen Activated Protein ◽  
Hepatocyte Growth ◽  
Darby Canine Kidney

Hepatocyte growth factor interacts with both heparan and dermatan sulphates, in addition to its specific signalling receptor, Met. However, the extent of glycosaminoglycan involvement in its biological activity remains uncertain. We have investigated the effects of exogenous glycosaminoglycan addition upon hepatocyte growth factor-stimulated motility of Madin-Darby canine kidney cells. Exogenous heparan/dermatan sulphate chains behave similarly as either potentiators or inhibitors of cell motility (depending upon the assay). Specific heparan sulphate oligosaccharides, of octasaccharide or larger, elicit similar effects, though with reduced potency. Additionally we have investigated the motility of cells made completely deficient in functional proteoglycans by metabolic inhibition of glycosaminoglycan sulphation, using chlorate. Such cells are completely unresponsive to hepatocyte growth factor, both in terms of downstream phosphorylation of mitogen-activated protein kinase and actual cell motility, though they do remain responsive to phorbol ester. Interestingly, although cell responsiveness to hepatocyte growth factor is not restored by exogenous heparan/dermatan sulphate chains, it is by an immobilised heparan sulphate proteoglycan substratum. These findings suggest that hepatocyte growth factor activity is not only critically dependent upon the presence of glycosaminoglycan, but specifically requires an intact proteoglycan structure located in close apposition to cell surface Met.

scholarly journals Activation of NF-κB Is Essential for Hepatocyte Growth Factor-Mediated Proliferation and Tubulogenesis

2002 ◽  
Vol 22 (4) ◽  
pp. 1060-1072 ◽  
Author(s):  
Markus Müller ◽  
Alessandro Morotti ◽  
Carola Ponzetto
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Transcriptional Activation ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Biological Responses ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Hepatocyte Growth

ABSTRACT Hepatocyte growth factor (HGF) and its receptor, Met, regulate a number of biological functions in epithelial and nonepithelial cells, such as survival, motility, proliferation, and tubular morphogenesis. The transcription factor NF-κB is activated in response to a wide variety of stimuli, including growth factors, and is involved in biological responses in part overlapping with those triggered by HGF. In this work we used the liver-derived MLP29 cell line to study the possible involvement of NF-κB in HGF/Met signaling. HGF stimulates NF-κB DNA binding and transcriptional activation via the canonical IκB phosphorylation-degradation cycle and via the extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase cascades. Phosphatidylinositol 3-kinase is not involved in Met-mediated NF-κB activation. Blockage of NF-κB activation in MLP29 cells by forced expression of the NF-κB super-repressor IκBα2A does not interfere with HGF-induced scatter but inhibits proliferation and tubulogenesis. Surprisingly, in the same cells NF-κB appears to be dispensable for the antiapoptotic function of HGF.

Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1405-1410 ◽  
Author(s):  
Patrick W. B. Derksen ◽  
Robert M. J. Keehnen ◽  
Ludo M. Evers ◽  
Marinus H. J. van Oers ◽  
Marcel Spaargaren ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Protein Kinase ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Growth Regulation ◽  
Plasma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Hepatocyte Growth

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.

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