Oncogenic Ras Downregulates Rac Activity, Which Leads to Increased Rho Activity and Epithelial–Mesenchymal Transition

The Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2000; 149(4):775-82.
Source: PubMed


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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Available from: Gerben C M Zondag
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    • "Ras along with rac1 or rho has been implicated in tumourigenesis [35]. Point mutations or overexpression can make these GTPases constitutively active [36]. "
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    ABSTRACT: Success of imatinib in chronic myeloid leukemia (CML) therapy has undoubtedly proved utility of signalling molecules as therapeutic targets. However, development of imatinib resistance and progression to blastic crisis are the current challenges in clinics. To develop therapeutic alternatives for CML, understanding of signalling events downstream of bcr-abl might be helpful. Current CML cell lines do not give comprehensive picture of signalling events involved in pathogenesis of CML. Hence, there is a major unmet need for a better preclinical model for CML. Here, we report on development of RIN9815/bcr-abl, a novel cell line model that mimics signalling events in CML PMNL. Studies on crucial signalling molecules i.e., ras, rac, rhoA and actin in this cell line identified rhoA as the key regulator involved in CML cell function as well as proliferation of both, imatinib sensitive and resistant cells. Hence, RIN9815/bcr-abl could serve as the unique preclinical model in understanding pathogenesis of CML and in drug development. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
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    • "This indicates that RhoA may be directly involved in renal tubular epithelial EMT. Furthermore, in contrast to the putative roles of Rac1 and Cdc42, which are believed to be involved in the establishment and maintenance of epithelial intercellular adhesions [35]–[37], activation of these proteins can also induce EMT accompanied by breakdown of cell-cell adhesion and rearrangement of the actin cytoskeleton [38]–[40]. Similar to these cells, EMT-like changes caused by small GTPases can occur in PMCs. A recent study by Zhang et al. [20] found that activation of RhoA in rat PMCs by TGF-β1 up-regulated α-SMA, vimentin, and collagen expression and down-regulated E-cadherin expression, suggesting that the RhoA/ROCK signaling pathway mediated EMT in rat PMCs in response to TGF-β1. "
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