Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 8 March 2011
Vol. 4, Issue 163, p. ec69
[DOI: 10.1126/scisignal.4163ec69]

EDITORS' CHOICE

MAPK Signaling Dual Mode of Oncogenesis

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Increased activity of the mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase (ERK) cascade due to activating mutations in the guanosine triphosphatase family of Ras proteins that lies upstream of the first kinase (Raf) in the ERK-MAPK cascade occurs in many forms of cancer. Kubota et al. show that, in addition to activating the pathway, oncogenic forms of Ras also prevent down-regulation of the pathway through SUMOylation of the second kinase in the pathway, MEK. Using a combination of in vitro and cultured cell assays, the authors showed that MEK1 and MEK2 were SUMOylated and that SUMOylated MEK was phosphorylated by the upstream kinase Raf effectively but exhibited poor activity toward its substrate ERK. Introduction of a SUMOylation-defective mutant enhanced signaling through the ERK pathway in various cultured cells. In vitro assays and experiments with cells expressing a form of MEK1 that was constitutively SUMOylated showed that both SUMOylated and unSUMOylated MEK1 were efficiently phosphorylated by Raf but that SUMOylated MEK had reduced activity toward and decreased interaction with its substrate ERK. The MAPK kinase kinase MEKK1 interacts with both MEK and Ubc9 (the E2 component of the SUMOylation machinery) and is itself SUMOylated, a common property of SUMO E3 ligases. Knockdown of MEKK1 reduced MEK SUMOylation in transfected cells, and in vitro studies showed that kinase-inactivated MEKK1 enhanced the efficiency of MEK1 SUMOylation. Thus, MEKK1 appears to SUMOylate MEK to limit activity of the ERK pathway. To determine whether MEK SUMOylation was involved in Ras-mediated carcinogenesis, the authors examined anchorage-independent growth of cells expressing various activating or dominant-negative mutants of components of the ERK pathway, which revealed that expression of the SUMOylation-defective mutant MEK1 enhanced colony formation when cells were transformed with activated forms of ErbB2 (a growth factor receptor), Raf-1, and B-Raf, but not with activated forms of Ras. Activated mutants of any of the three Ras family members prevented MEK1 SUMOylation, whereas dominant-negative mutants or mutants defective in membrane localization did not inhibit MEK SUMOylation. Oncogenic Ras enhanced the interaction of MEKK1 with Ubc9, which likely interfered with the SUMOylation cycle, which requires release and re-engagement of the E2 and E3 components. Cancer cell lines from patients with activating mutations in any of the three Ras isoforms had undetectable SUMOylated MEK1, and SUMOylation was restored by pharmacological inhibition of Ras activity with farnesyltransferase inhibitors or a combination of these inhibitors and inhibitors of geranylgeranyltransferases. These data reveal a negative feedback mechanism of the ERK pathway, a second mechanism by which oncogenic Ras promotes cancer, and suggest that enhancing MEK SUMOylation may provide a strategy in fighting cancers associated with excessive ERK pathway activity.

Y. Kubota, P. O’Grady, H. Saito, M. Takekawa, Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation. Nat. Cell Biol. 13, 282–291 (2011). [PubMed]

Citation: N. R. Gough, Dual Mode of Oncogenesis. Sci. Signal. 4, ec69 (2011).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882