scholarly journals Cell Confluence Regulates Hepatocyte Growth Factor-Stimulated Cell Morphogenesis in a β-Catenin-Dependent Manner

2006 ◽  
Vol 26 (24) ◽  
pp. 9232-9243 ◽  
Author(s):  
Shuta Ishibe ◽  
J. Erika Haydu ◽  
Akashi Togawa ◽  
Arnaud Marlier ◽  
Lloyd G. Cantley
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Glycogen Synthase ◽  
Organ Injury ◽  
Dependent Manner ◽  
Akt Activation ◽  
Nuclear Signaling ◽  
Gsk 3Β ◽  
High Level ◽  
Hepatocyte Growth

ABSTRACT Following organ injury, morphogenic epithelial responses can vary depending on local cell density. In the present study, the role of cell confluence in determining the responsiveness of renal epithelial cells to the dedifferentiating morphogenic signals of hepatocyte growth factor (HGF) was examined. Increasing confluence resulted in a greater tendency of cells to organize into epithelial tubes and a significant decrease in migratory responsiveness to HGF. Analysis of downstream signaling revealed that the HGF receptor c-Met was equally activated in confluent and nonconfluent cells following HGF stimulation but that phosphoinositide 3-kinase-dependent activation of Akt and Rac were selectively diminished in confluent cells. In nonconfluent cells treated with HGF, the high level of Akt activation resulted in inhibitory phosphorylation of glycogen synthase kinase 3β (GSK-3β) and increased β-catenin nuclear signaling. In contrast, confluent cells, in which HGF-stimulated Akt activation was diminished, displayed less inhibitory phosphorylation of GSK-3β and less nuclear signaling by β-catenin. Overexpression of β-catenin (SA), which cannot be phosphorylated by GSK-3β and targeted for ubiquitination, significantly increased migration in fully confluent cells. Thus, cells maintained at high confluence selectively downregulate signaling events such as Rac activation and β-catenin-dependent transcription that would otherwise promote cell dedifferentiation and migration.

Epithelial cell spreading induced by hepatocyte growth factor influences paxillin protein synthesis and posttranslational modification

2004 ◽  
Vol 287 (4) ◽  
pp. G886-G898 ◽  
Author(s):  
Ann M. Hopkins ◽  
Matthias Bruewer ◽  
G. Thomas Brown ◽  
A’Drian A. Pineda ◽  
Julie J. Ha ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Hepatocyte Growth Factor ◽  
Fluorescent Protein ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Epithelial Migration ◽  
Cell Matrix ◽  
Hepatocyte Growth

Superficial wounds in the gastrointestinal tract rapidly reseal by coordinated epithelial cell migration facilitated by cytokines such as hepatocyte growth factor (HGF)/scatter factor released in the wound vicinity. However, the mechanisms by which HGF promotes physiological and pathophysiologic epithelial migration are incompletely understood. Using in vitro models of polarized T84 and Caco-2 intestinal epithelia, we report that HGF promoted epithelial spreading and RhoA GTPase activation in a time-dependent manner. Inducible expression of enhanced green fluorescent protein-tagged dominant-negative RhoA significantly attenuated HGF-induced spreading. HGF expanded a zone of partially flattened cells behind the wound edge containing basal F-actin fibers aligned in the direction of spreading. Concomitantly, plaques positive for the focal adhesion protein paxillin were enhanced. HGF induced an increase in the translation of paxillin and, to a lesser extent, β1-integrin. This was independent of cell-matrix adhesion through β1-integrin. Subcellular fractionation revealed increased cosedimentation of paxillin with plasma membrane-containing fractions following HGF stimulation, without corresponding enhancements in paxillin coassociation with β1 integrin or actin. Tyrosine phosphorylation of paxillin was reduced by HGF and was sensitive to the Src kinase inhibitor PP2. With these taken together, we propose that HGF upregulates a free cytosolic pool of paxillin that is unaffiliated with either the cytoskeleton or focal cell-matrix contacts. Thus early spreading responses to HGF may partly relate to increased paxillin availability for incorporation into, and turnover within, dynamic cytoskeletal/membrane complexes whose rapid and transient adhesion to the matrix drives migration.

Hepatocyte growth factor induces an endothelin-mediated decline in glomerular filtration rate

2005 ◽  
Vol 288 (1) ◽  
pp. F8-F15 ◽  
Author(s):  
Purba Biswas ◽  
Abinash Roy ◽  
Rujun Gong ◽  
Angelito Yango ◽  
Evelyn Tolbert ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Glomerular Filtration Rate ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Initial Increase ◽  
Dependent Manner ◽  
Hemodynamic Changes ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays a crucial role in renal development, injury, and repair. HGF also serves a protective role in chronic renal disease by preventing tissue fibrosis. Endothelin-1 (ET-1), produced primarily by endothelial cells, is a potent vasoconstrictor that also acts as a proinflammatory peptide, promoting vascular injury and renal damage. In addition to mediating a variety of epithelial cell responses, HGF also induces hemodynamic changes that are poorly understood. The aim of the present study was to study the acute and chronic effects of HGF on ET-1 production in the kidney. We hypothesized that hemodynamic changes upon HGF treatment are likely mediated by immediate ET-1 release, whereas protection from renal fibrosis in rats chronically treated with HGF is likely due to suppression of ET-1 production. Acute HGF infusion into rats caused a decline in blood pressure that was enhanced by pretreatment with bosentan (an endothelin A and B receptor antagonist). HGF infusion also resulted in a decline in glomerular filtration rate (GFR) that could be entirely prevented by bosentan, suggesting that HGF acutely increases production and/or release of ET-1, which then mediates the observed decline in GFR. In cultured glomerular endothelial cells, HGF induced ET-1 production in a dose-dependent manner. Moreover, although there was an initial increase in ET-1 production upon HGF treatment, longer administration suppressed ET-1 production. This finding was consistent with the observation in vivo of a decrease in ET-1 production in renal parenchyma of rats chronically treated with HGF. Our data suggest both a hemodynamic and biological role for HGF-mediated ET-1 regulation.

scholarly journals Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4238
Author(s):  
Masahiro Mizuno ◽  
Behnoush Khaledian ◽  
Masao Maeda ◽  
Takanori Hayashi ◽  
Seiya Mizuno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Stem Cell ◽  
Growth Factor ◽  
Cancer Stem Cell ◽  
Hepatocyte Growth Factor ◽  
Tumor Formation ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Hepatocyte Growth

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.

Effects of hepatocyte growth factor on the expression of matrix metalloproteinases and their tissue inhibitors during the endometrial cancer invasion in a three-dimensional coculture

2003 ◽  
Vol 13 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Y.-H. Park ◽  
H.-S. Ryu ◽  
D.-S. Choi ◽  
K.-H. Chang ◽  
D.-W. Park ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stromal Cells ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Hepatocyte Growth

Matrix metalloproteinase (MMP)-2 and -9 are secreted and translocated from endometrial stromal cells to HEC-1 A cells in a steroid-dependent manner. We investigated the paracrine effect of hepatocyte growth factor (HGF) on MMPs and metalloproteinase tissue inhibitor (TIMP) expression in stromal and endometrial cancer cells, and correlated with cancer cell invasiveness in three-dimensional (3D) coculture. The 3D coculture of endometrial stromal and cancer cell lines (HEC-1 A, HEC-IB, or KLE) were maintained in the presence or absence of HGF. The expression of MMP-2 and -9, MT1-MMP, TIMP-1 and -2 were examined by RT-PCR and zymography. Under the same conditions, invasion of the cancer cells was quantified by Boyden's chamber assay. HGF strongly induced MMP-9 mRNA expression in stromal cells, but had little effect on MMP-2 mRNA. MT1-MMP mRNA was detected only in KLE and stromal cells, which was also increased by HGF. TIMP-1 and -2 mRNAs was ubiquitous with no dependence on HGF. Zymographic analysis of MMPs showed that activation of MMP-2 and -9 was enhanced by HGF. A significant increase in invasion of all three cancer cells with HGF was observed. The effect of HGF on the invasiveness of 3D cocultured endometrial cancer cells and stromal cells appears to be due to induction of MMP-9 mRNA expression in stromal cells and /or increased activation of MMP-2 and MMP-9 by proteolytic digestion.

scholarly journals Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

2020 ◽  
Vol 21 (4) ◽  
pp. 1289
Author(s):  
Amit Koren-Iton ◽  
Shiran Salomon-Zimri ◽  
Alex Smolar ◽  
Efrat Shavit-Stein ◽  
Amir Dori ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Apoe Genotype ◽  
Dependent Manner ◽  
Fiber Density ◽  
Akt Activation ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Gsk 3Β

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

HIGH LEVEL OF THE SERUM HEPATOCYTE GROWTH FACTOR PREDICTS THE DEVELOPMENT OF METABOLIC SYNDROME:THE TANUSHIMARU COHORT STUDY

2011 ◽  
Vol 29 ◽  
pp. e149
Author(s):  
E. Tsukagawa ◽  
H. Adachi ◽  
Y. Hirai ◽  
M. Enomoto ◽  
A. Fukami ◽  
...  
Keyword(s):  
Cohort Study ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
High Level ◽  
Hepatocyte Growth
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