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Mol Biol Cell. 2019 Feb 20:mbcE18100676. doi: 10.1091/mbc.E18-10-0676. [Epub ahead of print]

Isoform-specific Ras signaling is growth factor dependent.

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Division of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, L69 3BX, UK.
Institute of Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Integrative Research Institute for the Life Sciences, Humboldt-Universität zu Berlin, 10099 Berlin, Institute for Theoretical Biology, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
Department of Biological Sciences, University of Chester, CH1 4BJ, UK.


HRAS, NRAS and KRAS isoforms are almost identical proteins that are ubiquitously expressed and activate a common set of effectors. In vivo studies have revealed that they are not biologically redundant; however, the isoform-specificity of Ras signaling remains poorly understood. Using a novel panel of isogenic SW48 cell lines endogenously expressing wild type or G12V mutated activated Ras isoforms we have performed a detailed characterization of endogenous isoform-specific mutant Ras signaling. We find that despite displaying significant Ras activation, the downstream outputs of oncogenic Ras mutants are minimal in the absence of growth factor inputs. The lack of mutant KRAS-induced effector activation observed in SW48 cells appears to be representative of a broad panel of colon cancer cell lines harboring mutant KRAS. For MAP kinase pathway activation in KRAS mutant cells, the requirement for co-incident growth factor stimulation occurs at an early point in the Raf activation cycle. Finally, we find that Ras isoform-specific signaling was highly context dependent and did not conform to the dogma derived from ectopic expression studies.


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