Abstract
Activated versions of the similar GTPases, H-Ras and R-Ras, have differing effects on biological phenotypes: Activated H-Ras strongly transforms many fibroblast cell lines causing dramatic changes in cell shape and cytoskeletal organization. In contrast, R-Ras transforms fewer cell lines and the transformed cells display only some of the morphological changes associated with H-Ras transformation. H-Ras cells can survive in the absence of serum whereas R-Ras cells seem to die by an apoptotic-like mechanism in response to removal of serum. H-Ras can suppress integrin activation and R-Ras specifically antagonizes this effect. To map sequences responsible for these differences we have generated and investigated a panel of H-Ras and R-Ras chimeras. We found that the C-terminal 53 amino acids of R-Ras were necessary and sufficient to specify the contrasting biological properties of R-Ras with respect to focus morphology, reactive oxygen species (ROS) production and reversal of H-Ras-induced integrin suppression. Surprisingly, we found chimeras in which the focus formation and integrin-mediated phenotypes were separated, suggesting that different effectors could be involved in mediating these responses. An integrin profile of H-Ras and R-Ras cell pools showed no significant differences; both activated H-Ras and R-Ras expressing cells were found to have reduced β1 activity, suggesting that the activity state of the β1 subunit is not sufficient to direct an H-Ras transformed cell morphology.
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Acknowledgements
The PhD fellowship of M Hansen was funded by grant 9600821 from the Danish Medical Research council to BM Willumsen. M Hansen received travel grants from the Plasmid Foundation. The work was supported by grant 97 100 13 from the Danish Cancer Society and grant 9600821 from the Danish Medical Research council to BM Willumsen, grants CA 61951 and CA 76092 from the NIH to AD Cox, and HL 31950 and HL 48728 to MH Ginsberg.
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Hansen, M., Rusyn, E., Hughes, P. et al. R-Ras C-terminal sequences are sufficient to confer R-Ras specificity toH-Ras. Oncogene 21, 4448–4461 (2002). https://doi.org/10.1038/sj.onc.1205538
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DOI: https://doi.org/10.1038/sj.onc.1205538
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