Proteins of the Rho family regulate cytoskeletal rearrangements in response to receptor stimulation and are involved in the establishment and maintenance of epithelial cell morphology. We recently showed that Rac is able to downregulate Rho activity and that the reciprocal balance between Rac and Rho activity is a major determinant of cellular morphology and motility in NIH3T3 fibroblasts. Using biochemical pull-down assays, we analyzed the effect of transient and sustained oncogenic Ras signaling on the activation state of Rac and Rho in epithelial MDCK cells. In contrast to the activation of Rac by growth factor-induced Ras signaling, we found that sustained signaling by oncogenic RasV12 permanently downregulates Rac activity, which leads to upregulation of Rho activity and epithelial–mesenchymal transition. Oncogenic Ras decreases Rac activity through sustained Raf/MAP kinase signaling, which causes transcriptional downregulation of Tiam1, an activator of Rac in epithelial cells. Reconstitution of Rac activity by expression of Tiam1 or RacV12 leads to downregulation of Rho activity and restores an epithelial phenotype in mesenchymal RasV12- or RafCAAX-transformed cells. The present data reveal a novel mechanism by which oncogenic Ras is able to interfere with the balance between Rac and Rho activity to achieve morphological transformation of epithelial cells.
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15 May 2000
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May 15 2000
Oncogenic Ras Downregulates Rac Activity, Which Leads to Increased Rho Activity and Epithelial–Mesenchymal Transition
Gerben C.M. Zondag,
Gerben C.M. Zondag
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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Eva E. Evers,
Eva E. Evers
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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Jean P. ten Klooster,
Jean P. ten Klooster
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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Lennert Janssen,
Lennert Janssen
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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Rob A. van der Kammen,
Rob A. van der Kammen
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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John G. Collard
John G. Collard
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
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Gerben C.M. Zondag
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
Eva E. Evers
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
Jean P. ten Klooster
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
Lennert Janssen
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
Rob A. van der Kammen
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
John G. Collard
aThe Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands
Abbreviations used in this paper: GST, glutathione S transferase; HGF, hepatocyte growth factor; PI3, phosphatidylinositol 3.
Received:
December 21 1999
Revision Requested:
March 20 2000
Accepted:
March 30 2000
Online ISSN: 1540-8140
Print ISSN: 0021-9525
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Cell Biol (2000) 149 (4): 775–782.
Article history
Received:
December 21 1999
Revision Requested:
March 20 2000
Accepted:
March 30 2000
Citation
Gerben C.M. Zondag, Eva E. Evers, Jean P. ten Klooster, Lennert Janssen, Rob A. van der Kammen, John G. Collard; Oncogenic Ras Downregulates Rac Activity, Which Leads to Increased Rho Activity and Epithelial–Mesenchymal Transition. J Cell Biol 15 May 2000; 149 (4): 775–782. doi: https://doi.org/10.1083/jcb.149.4.775
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