Isoform-specific Ras signaling is growth factor dependent

Molecular Biology of the Cell
Fiona E HoodIan A Prior

Abstract

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 coincident 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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Citations

Sep 26, 2019·Science Signaling·Thomas McFallEdward C Stites
Jun 12, 2020·Cancer Metastasis Reviews·Marcell BaranyiBalázs Hegedűs
Jan 13, 2021·Advances in Biological Regulation·Natalia KuhnReinhold Schäfer
Nov 5, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Imran KhanJohn P O'Bryan
Oct 31, 2020·Biochemical Society Transactions·Swati Singh, Matthew J Smith
Sep 14, 2021·The Journal of Cell Biology·Sachin SurveAlexander Sorkin
Nov 5, 2021·PLoS Computational Biology·Mathurin DorelNils Blüthgen

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Methods Mentioned

BETA
GTPases
nucleotide exchange
Protein Assay
Protein Array
enzyme-linked immunosorbent assays
coimmunoprecipitation
Assay

Software Mentioned

DepMap
ImageStudio
ImageJ
R package STASNet

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