2026-06-14T03:46:26Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/267632025-12-18T12:56:53Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Fernández-Pisonero, Isabel author Lorenzo-Martín, L Francisco author Drosten, Mattias author Santos, Eugenio author Barbacid, Mariano author Alarcón, Balbino author Bustelo, Xosé R author 2025-07 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. Oncogene . 2025 Jul;44(24):1905-1921. Oncogene 40164870 https://hdl.handle.net/20.500.12105/26763 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.