Regulation of Scatter Factor/Hepatocyte Growth Factor Responses by Ras, Rac, and Rho in MDCK Cells

Ridley, Anne J.; Comoglio, Paolo M.; Hall, Alan

doi:10.1128/mcb.15.2.1110

Cited by 509 publications

(477 citation statements)

References 58 publications

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“…At 16 h, the staining of E-cadherin at the cell-cell adhesion sites became indistinct and most cells scattered (Figure 4g). These results are consistent with the previous observations (Ridley et al, 1995;Imamura et al, 1998). Stimulation of sMDCK-RacDA-1 cells with HGF/SF for 16 h caused slight spreading of the cells and weaker staining of E-cadherin at the cell-cell adhesion sites (Figure 4h).…”

Section: Increased Accumulation Of E-cadherin and B-catenin At Cell-csupporting

confidence: 93%

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

et al. 1999

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The Rho small G protein family consists of the Rho, Rac, and Cdc42 subfamilies and regulates various cell functions through reorganization of the actin cytoskeleton. We previously showed that the Rho subfamily regulates the formation of stress ®bers and focal adhesions whereas the Rac subfamily regulates the Ecadherin-based cell-cell adhesion in MDCK cells. We studied here the function of the Cdc42 subfamily, consisting of two members, Cdc42Hs and G25k, in cell adhesion, migration, and morphology of MDCK cells. For this purpose, we made and used MDCK cell lines stably expressing each of dominant active mutants of Cdc42Hs (sMDCK-Cdc42HsDA) and G25K (sMDCK-G25KDA). Actin ®laments at the cell-cell adhesion sites increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Both E-cadherin and b-catenin, adherens junctional proteins, at the cell-cell adhesion sites also increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Electron microscopic analysis revealed that sMDCKCdc42HsDA cells tightly contacted with each other throughout the lateral membranes. Moreover, both the HGF-and TPA-induced disruption of the cadherin-based cell-cell adhesion and the subsequent cell migration were inhibited in both sMDCK-Cdc42HsDA and -G25KDA cells. Co-expression of the dominant negative mutant of Rac1, a member of the Rac subfamily, with the dominant active mutant of Cdc42Hs did not inhibit the increased accumulation of actin ®laments at the cell-cell adhesion sites. These results suggest that the Cdc42 subfamily is involved in the cadherin-based cell-cell adhesion in a manner independent of the Rac subfamily. Furthermore, the cells were frequently enveloped by the large multinuclear cells in both sMDCK-Cdc42HsDA and -G25KDA cells. Video microscopic analysis revealed that the cells were engulfed by the large cells during cytokinesis.

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Section: Increased Accumulation Of E-cadherin and B-catenin At Cell-csupporting

confidence: 93%

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

et al. 1999

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“…Various intracellular signalling pathways are activated by Met and mediate a speci®c cell response. In epithelial cells, it is established that scattering is dependent on phosphatidylinositol-3-OH kinase and Rac activation (Ridley et al, 1995), while growth requires the stimulation of the Ras-MAPK (Ponzetto et al, 1996) cascade and the STAT pathway is necessary for tubulogenesis (Boccaccio et al, 1998). To understand how TGF b 2 inhibits HGF, we elucidated which intracellular signalling pathways are able to discriminate between HGF-induced cell migration and proliferation in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

Manganini

Maier

2000

Oncogene

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Angiogenesis is a highly controlled event which depends on the proper equilibrium of activators and inhibitors present within the microenvironment. Hepatocyte Growth Factor (HGF) activates migration and proliferation of endothelial cells and is angiogenic, acting through the tyrosine kinase receptor encoded by the Met protooncogene. To get insights into the molecular mechanisms involved in HGF-induced angiogenesis, we searched for cDNAs di erentially expressed in human endothelial cells exposed to HGF, a potent angiogenic factor. We found that HGF-treated endothelial cells upregulated the expression of Transforming Growth Factor (TGF) b 2 . To understand the signi®cance of this ®nding, we cultured endothelial cells with HGF and TGF b 2 simultaneously. We found that TGF b 2 impairs HGFdependent proliferative and migratory responses. TGF b 2 did not prevent the tyrosine phosphorylation of Met, but it inhibited some signalling pathways activated by HGF. We show that endothelial proliferation induced by HGF required the activation of the MAPK cascade, while HGF-induced endothelial migration was dependent on the tyrosine phosphorylation of Src. Indeed, TGF b 2 inhibited HGF e ects because it prevented HGF-induced MAP kinase activation and tyrosine phosphorylation of Src. We suggest that the induction of TGF b 2 by HGF in endothelial cells may represent a physiologic mechanism to counterbalance HGF angiogenic activity. Oncogene (2000) 19, 124 ± 133.

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“…Cdc42 is required for cell polarity and stimulates filopodial protrusions, whereas Rac1 promotes lamellipodial extensions rich in filamentous actin. A basal level of RhoA activity is needed for fibroblast migration, although too much RhoA activity impedes migration [Takaishi et al, 1994;Ridley et al, 1995;Nobes and Hall, 1999]. Unrestrained RhoA activity may result in a particularly high cortical tension barrier at the leading edge, as well as lead to excessive adhesion through focal adhesions.…”

Section: Introductionmentioning

confidence: 99%

The role of RhoA in the regulation of cell morphology and motility

Tkach¹,

Bock²,

Berezin³

2005

Cell Motil. Cytoskeleton

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Members of the Rho family of small GTPases are key regulators of the actin cytoskeleton, particularly in relation to the cell shape changes and the adhesion dynamic that drive cell migration. Here, we report the effect of activation or inhibition of the function of RhoA on cell motility and morphology. Both in the presence and the absence of serum, expression of constitutively active RhoA dramatically inhibited L929 fibroblasts' cell motility, and induced a rounding of the cells and a decrease in the number of processes per cell. In contrast, expression of a dominant negative mutant of RhoA had no effect on cell motility or morphology in steady-state conditions with or without serum in the medium. Inhibition of p160ROCK, a kinase effector of RhoA, only partially inhibited cell migration. Conversely, when cells were submitted to a period of serum deprivation followed by addition of serum, inhibition of endogenous RhoA by expression of the dominant negative mutant of RhoA impeded cell motility after serum stimulation. Thus, RhoA activity is required for stimulation of cell locomotion by serum factors. It was also observed that the addition of serum factors to quiescent L929 and NR6wtEGFR fibroblasts resulted in a delayed motility response of several hours compared to the immediately induced morphological changes, indicating the absence of a previously assumed direct correlation between changes in cell motility and cell morphology in response to serum addition. The motility response of L929 and NR6wtEGFR fibroblasts to serum stimulation required protein synthesis. Cell Motil.

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Regulation of Scatter Factor/Hepatocyte Growth Factor Responses by Ras, Rac, and Rho in MDCK Cells

Cited by 509 publications

References 58 publications

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

The role of RhoA in the regulation of cell morphology and motility

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