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Divergent effects of intrinsically active MEK variants on developmental Ras signaling

Author(s): Goyal, Yogesh; Jindal, Granton A; Pelliccia, José L; Yamaya, Kei; Yeung, Eyan; et al

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Abstract: Germline mutations in Ras pathway components are associated with a large class of human developmental abnormalities, known as RASopathies, that are characterized by a range of structural and functional phenotypes, including cardiac defects and neurocognitive delays1,2. Although it is generally believed that RASopathies are caused by altered levels of pathway activation, the signaling changes in developing tissues remain largely unknown3,4. We used assays with spatiotemporal resolution in Drosophila melanogaster (fruit fly) and Danio rerio (zebrafish) to quantify signaling changes caused by mutations in MAP2K1 (encoding MEK), a core component of the Ras pathway that is mutated in both RASopathies and cancers in humans5,6. Surprisingly, we discovered that intrinsically active MEK variants can both increase and reduce the levels of pathway activation in vivo. The sign of the effect depends on cellular context, implying that some of the emerging phenotypes in RASopathies may be caused by increased, as well as attenuated, levels of Ras signaling.
Publication Date: Mar-2017
Electronic Publication Date: 6-Feb-2017
Citation: Goyal, Yogesh, Jindal, Granton A, Pelliccia, José L, Yamaya, Kei, Yeung, Eyan, Futran, Alan S, Burdine, Rebecca D, Schüpbach, Trudi, Shvartsman, Stanislav Y. (2017). Divergent effects of intrinsically active MEK variants on developmental Ras signaling. Nature Genetics, 49 (3), 465 - 469. doi:10.1038/ng.3780
DOI: doi:10.1038/ng.3780
ISSN: 1061-4036
EISSN: 1546-1718
Pages: 465 - 469
Type of Material: Journal Article
Journal/Proceeding Title: Nature Genetics
Version: Author's manuscript

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