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A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth

Oncogene volume 20, pages 188–197 (2001)Cite this article

Abstract

Here, we report the identification and characterization of a new member of the RalGDS-family, which is widely expressed and interacts strongly and selectively with the GTP-bound forms of M-Ras and p21 Ras. This Ras pathway modulator (RPM), also termed RGL3, exhibited Ras-binding and catalytic domains typical of the RalGDS-family of guanine nucleotide exchange factors, and was most similar to Rlf (RalGDS-like factor), but was distinguished by a unique proline-rich region with multiple candidate SH3-domain binding sites. RPM/RGL3 resembled AF-6 and Nore1 in interacting strongly with constitutively active M-Ras and p21 Ras. In contrast to Rlf, transiently expressed RPM/RGL3 did not activate an Elk-1-inducible reporter gene alone or in combination with activated p21 Ras, but strongly inhibited induction of this reporter gene by co-expression of activated H-Ras or MEKK-1. This inhibitory effect was independent of the Ras binding domain and required a second signal provided by p21 Ras or MEKK-1, but not Raf-1 or M-Ras. Expression of RPM/RGL3 also strongly inhibited cell growth of fibroblasts transformed by an activated Src Y527F. Thus, RPM/RGL3 is a novel potential effector of both p21 Ras and M-Ras with the novel function of negatively regulating Elk-1-dependent gene induction downstream of p21 Ras or MEKK-1.

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Acknowledgements

We are grateful to Dr A Ambrosini (DiBiT, H San Raffaele, Milan, Italy) for H-Ras constructs and Dr J Bos (Utrecht, The Netherlands) for the Rlf expression construct. We would like to thank Annette Y Schallhorn for helpful discussions and critical reading of the manuscript. This work was supported by a grant from the Medical Research Council, Canada. The nucleotide sequence reported in this paper has been submitted to GenBank with the accession number AF239661.

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  1. The Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, V6T 1Z3, BC, Canada

    Götz RA Ehrhardt, Christian Korherr, James S Wieler, Michèle Knaus & John W Schrader

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Ehrhardt, G., Korherr, C., Wieler, J. et al. A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth. Oncogene 20, 188–197 (2001). https://doi.org/10.1038/sj.onc.1204053

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