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Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking
Isabel Fernández-Pisonero1,2,3, L Francisco Lorenzo-Martín1,2,3,4, Mattias Drosten1,2,3
1Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, CSIC and Universidad de Salamanca, Salamanca, Spain.
Oncogene
|March 31, 2025
Summary
R-RAS2/TC21 is crucial for cell proliferation and adhesion in mouse embryonic fibroblasts (MEFs). Its absence exacerbates defects in cells lacking RAS signaling, highlighting its essential role in cell viability.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- R-RAS2/TC21, part of the R-RAS subfamily, shares traits with RAS proteins but its function in normal cells is unclear.
- The functional overlap between R-RAS2/TC21, R-RAS, and classical RAS proteins remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of R-RAS2/TC21 in mouse embryonic fibroblasts (MEFs) using genetic manipulation.
- To determine the functional redundancy between R-RAS2/TC21, R-RAS, and RAS subfamily proteins.
Main Methods:
- Utilized loss-of-function (gene knockout) and gain-of-function (ectopic expression) approaches in primary MEFs.
- Generated MEFs from Rras2-/-, Rras-/-, and Rras-/-; Rras2-/- embryos for analysis.
Main Results:
- Endogenous R-RAS2/TC21 is essential for activating the PI3K-AKT pathway, cell proliferation, and adhesion in MEFs.
- R-RAS2/TC21 depletion worsened defects in MEFs lacking H-, K-, and N-RAS.
- Active R-RAS2/TC21, but not R-RAS, rescued these defects, involving TP53 inhibition and PI3K, mTORC, and MEK/ERK signaling.
Conclusions:
- R-RAS2/TC21, R-RAS, and RAS GTPases have distinct roles in MEF function.
- R-RAS2/TC21 provides critical support for proliferation and viability in RAS-deficient MEFs.
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