scholarly journals Activation of Both MAP Kinase and Phosphatidylinositide 3-Kinase by Ras Is Required for Hepatocyte Growth Factor/Scatter Factor–induced Adherens Junction Disassembly

1998 ◽  
Vol 9 (8) ◽  
pp. 2185-2200 ◽  
Author(s):  
Sandra Potempa ◽  
Anne J. Ridley
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Map Kinase ◽  
Adherens Junctions ◽  
Adherens Junction ◽  
Dominant Negative ◽  
Cell Junctions ◽  
Scatter Factor ◽  
Cell Scattering ◽  
Hepatocyte Growth

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the motility of epithelial cells, initially inducing centrifugal spreading of colonies followed by disruption of cell–cell junctions and subsequent cell scattering. In Madin–Darby canine kidney cells, HGF/SF-induced motility involves actin reorganization mediated by Ras, but whether Ras and downstream signals regulate the breakdown of intercellular adhesions has not been established. Both HGF/SF and V12Ras induced the loss of the adherens junction proteins E-cadherin and β-catenin from intercellular junctions during cell spreading, and the HGF/SF response was blocked by dominant-negative N17Ras. Desmosomes and tight junctions were regulated separately from adherens junctions, because they were not disrupted by V12Ras. MAP kinase, phosphatidylinositide 3-kinase (PI 3-kinase), and Rac were required downstream of Ras, because loss of adherens junctions was blocked by the inhibitors PD098059 and LY294002 or by dominant-inhibitory mutants of MAP kinase kinase 1 or Rac1. All of these inhibitors also prevented HGF/SF-induced cell scattering. Interestingly, activated Raf or the activated p110α subunit of PI 3-kinase alone did not induce disruption of adherens junctions. These results indicate that activation of both MAP kinase and PI 3-kinase by Ras is required for adherens junction disassembly and that this is essential for the motile response to HGF/SF.

Phosphatidylinositol 3-kinase Contributes to Erk1/Erk2 MAP Kinase Activation Associated with Hepatocyte Growth Factor-induced Cell Scattering

1999 ◽  
Vol 11 (12) ◽  
pp. 885-890 ◽  
Author(s):  
Szabolcs Sipeki ◽  
Erzsébet Bander ◽  
László Buday ◽  
Gyöngyi Farkas ◽  
Ernõ Bácsy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Map Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Kinase Activation ◽  
Cell Scattering ◽  
Hepatocyte Growth ◽  
Phosphatidylinositol 3

Hepatocyte growth factor/scatter factor and its interaction with heparan sulphate and dermatan sulphate

2003 ◽  
Vol 31 (2) ◽  
pp. 352-353 ◽  
Author(s):  
K. Catlow ◽  
J.A. Deakin ◽  
M. Delehedde ◽  
D.G. Fernig ◽  
J.T. Gallagher ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Map Kinase ◽  
Heparan Sulphate ◽  
Dermatan Sulphate ◽  
Scatter Factor ◽  
Activation Assay ◽  
Map Kinase Pathway ◽  
Hepatocyte Growth ◽  
Kinase Pathway

Hepatocyte growth factor (HGF)/scatter factor (SF) is a unique growth factor, in that it binds both heparan sulphate (HS) and dermatan sulphate (DS). The sequences in HS and DS that specifically interact with and modulate HGF/SF activity have not yet been fully identified. Ascidian DS, which uniquely possesses O-sulphation at C-6 (and not C-4) of its N-acetylgalactosamine unit, was analysed for HGF/SF-binding activity in the biosensor. The kinetic analysis revealed a strong, biologically relevant interaction with an equilibrium dissociation constant (Kd) of approx. 1 nM. An Erk activation assay also demonstrated stimulation of the MAP kinase pathway downstream of the Met receptor following addition of both HGF/SF and ascidian DS to the glycosaminoglycan-deficient CHO-745 mutant cell line. Furthermore, the activation of Met and the MAP kinase pathway by HGF/SF and ascidian DS leads to a cellular response in the form of migration.

scholarly journals The β-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis

2000 ◽  
Vol 350 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Stephen M. RIORDAN ◽  
Sukhwinderjit LIDDER ◽  
Roger WILLIAMS ◽  
George G. SKOUTERIS
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Sh2 Domain ◽  
Dominant Negative ◽  
Domain Growth ◽  
Dominant Negative Mutant ◽  
Wild Type ◽  
Scatter Factor ◽  
Sh3 Domains ◽  
Hepatocyte Growth

CrkII, a 40kDa adaptor possessing a Src homology (SH)2 domain followed by two SH3 domains, although not endowed with catalytic activity, participates in intracellular signalling, presumably by activating the Ras pathway. CrkII was found to be phosphorylated in response to hepatocyte growth factor/scatter factor (HGF/SF) and to associate with the beta-subunit of the HGF receptor (MET). CrkII associated with p145βMET via its SH2 domain. Growth-factor-receptor-bound protein 2 (Grb2) co-immunoprecipitated with CrkII species. By transient transfection of A431 human epidermoid carcinoma cells with wild-type and dominant-negative Grb2 expression constructs lacking either the SH2 or SH3 domains, we have concluded that Grb2 does not contribute to the ‘presentation’ of CrkII to p145βMET. Overexpression of wild-type CrkII in A431 cells enhanced HGF/SF-induced proliferation, while a CrkII dominant-negative mutant lacking the SH2 domain prevented a similar proliferating response to HGF/SF. The effect of CrkII on HGF/SF-induced proliferation was also abolished in cells co-expressing CrkII and Son-of-sevenless lacking the guanine exchange domain, suggesting that CrkII is likely to induce cell proliferation partly via the Ras/mitogen-activated protein kinase route.

scholarly journals The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)–c-Met Signaling for Cell Survival and DNA Repair

2001 ◽  
Vol 21 (15) ◽  
pp. 4968-4984 ◽  
Author(s):  
Saijun Fan ◽  
Yong Xian Ma ◽  
Min Gao ◽  
Ren-Qi Yuan ◽  
Qinghui Meng ◽  
...  
Keyword(s):  
Dna Repair ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Survival ◽  
Binding Domain ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Scatter Factor ◽  
Factor C ◽  
Hepatocyte Growth

ABSTRACT Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIα inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.

scholarly journals Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells.

1995 ◽  
Vol 15 (2) ◽  
pp. 1110-1122 ◽  
Author(s):  
A J Ridley ◽  
P M Comoglio ◽  
A Hall
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mdck Cells ◽  
Cell Junctions ◽  
Stress Fibers ◽  
Scatter Factor ◽  
Actin Reorganization ◽  
Membrane Ruffling ◽  
Additional Signal ◽  
Hepatocyte Growth

Scatter factor/hepatocyte growth factor (SF/HGF) stimulates the motility of epithelial cells, initially inducing centrifugal spreading of cell colonies followed by disruption of cell-cell junctions and subsequent cell scattering. These responses are accompanied by changes in the actin cytoskeleton, including increased membrane ruffling and lamellipodium extension, disappearance of peripheral actin bundles at the edges of colonies, and an overall decrease in stress fibers. The roles of the small GTP-binding proteins Ras, Rac, and Rho in regulating responses to SF/HGF were investigated by microinjection. Inhibition of endogenous Ras proteins prevented SF/HGF-induced actin reorganization, spreading, and scattering, whereas microinjection of activated H-Ras protein stimulated spreading and actin reorganization but not scattering. When a dominant inhibitor of Rac was injected, SF/HGF- and Ras-induced spreading and actin reorganization were prevented, although activated Rac alone did not stimulate either response. Microinjection of activated Rho inhibited spreading and scattering, while inhibition of Rho function led to the disappearance of stress fibers and peripheral bundles but did not prevent SF/HGF-induced motility. We conclude that Ras and Rac act downstream of the SF/HGF receptor p190Met to mediate cell spreading but that an additional signal is required to induce scattering.

scholarly journals Characterization of the Scatter Factor/Hepatocyte Growth Factor Gene Promoter

1995 ◽  
Vol 270 (2) ◽  
pp. 830-836 ◽  
Author(s):  
Antje Plaschke-Schlütter ◽  
Jürgen Behrens ◽  
Ermanno Gherardi ◽  
Walter Birchmeier
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Gene Promoter ◽  
Scatter Factor ◽  
Factor Gene ◽  
Growth Factor Gene ◽  
Hepatocyte Growth

scholarly journals Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

1997 ◽  
Vol 185 (12) ◽  
pp. 2121-2131 ◽  
Author(s):  
Robbert van der Voort ◽  
Taher E.I. Taher ◽  
Robert M.J. Keehnen ◽  
Lia Smit ◽  
Martijn Groenink ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Scatter Factor ◽  
Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

scholarly journals Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor

2001 ◽  
Vol 159 (2) ◽  
pp. 579-590 ◽  
Author(s):  
Glenn A. Gmyrek ◽  
Marc Walburg ◽  
Craig P. Webb ◽  
Hsiao-Man Yu ◽  
Xueke You ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Scatter Factor ◽  
Prostate Epithelial Cells ◽  
Hepatocyte Growth ◽  
Malignant Prostate

Hepatocyte Growth Factor/Scatter Factor Stimulates Hair Growth of Mouse Vibrissae in Organ Culture

1994 ◽  
Vol 103 (3) ◽  
pp. 306-309 ◽  
Author(s):  
Toshimasa Jindo ◽  
Ryoji Tsuboi ◽  
Ryusuke Imai ◽  
Kenji Takamori ◽  
Jeffrey S Rubin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Organ Culture ◽  
Hepatocyte Growth Factor ◽  
Hair Growth ◽  
Scatter Factor ◽  
Hepatocyte Growth
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