2026-06-14T05:17:55Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/267632025-12-18T12:56:53Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991
Repisalud
author
Fernández-Pisonero, Isabel
author
Lorenzo-Martín, L Francisco
author
Drosten, Mattias
author
Santos, Eugenio
author
Barbacid, Mariano
author
Alarcón, Balbino
author
Bustelo, Xosé R
funder
La Caixa
funder
Asociaciacion Española Contra el Cancer
funder
MCIN/AEI
2025-06-18T08:46:08Z
2025-06-18T08:46:08Z
2025-07
Oncogene . 2025 Jul;44(24):1905-1921.
Oncogene
40164870
https://hdl.handle.net/20.500.12105/26763
R-RAS2/TC21, a member of the R-RAS subfamily of GTP-binding proteins, shares structural and signaling properties with the RAS subfamily proteins H-, K-, and N-RAS. However, little information is available regarding its role in normal cells and the level of functional redundancy with R-RAS and classical RAS proteins. In this work, we used loss and gain-of-function approaches to assess these issues in mouse embryonic fibroblasts (MEFs). Using primary MEFs from Rras2, Rras or Rras; Rras2 embryos, we show here that endogenous R-RAS2/TC21 is required for activation of the phosphatidylinositol 3 kinase (PI3K)-AKT axis, the proliferation, and the adhesion properties of these cells. Endogenous R-RAS does not influence any of these cell parameters. We also show that the depletion of R-RAS2/TC21 worsens the proliferative and morphological defects elicited by the combined loss of H-, K- and N-RAS proteins in MEFs. Conversely, the ectopic expression of an active version of R-RAS2/TC21, but not of R-RAS, overcomes such defects. This rescue activity involves the inhibition of the tumor suppressor TP53 and is PI3K-, mTORC-, and MEK/ERK-dependent. These results indicate that R-RAS2/TC21, R-RAS, and RAS subfamily GTPases play different roles in MEFs. They also show that R-RAS2 provides subsidiary signals that are essential for the short-term proliferation and long-term viability of MEFs lacking RAS signaling.
eng
HUMAN R-RAS
TC21
ACTIVATION
TRANSFORMATION
MIGRATION
PROLIFERATION
TC21/R-RAS2
EXPRESSION
KINASE
Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking RAS proteins.
research article
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URL
https://repisalud.isciii.es/bitstreams/6337399e-7637-4560-a3e4-8b86bb1b37f5/download
File
MD5
f2d2f53ef206da44f802d1d6ba7e9b7e
13359057
application/pdf
ActiveRRAS2TC21prevents_2025.pdf