Scholarlink

<p>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 <i>Rras2</i><sup>–/–</sup>, <i>Rras</i><sup>–/–</sup> or <i>Rras</i><sup>–/–</sup>; <i>Rras2</i><sup>–/–</sup> 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.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Active R-RAS2/TC21 prevents cell cycle arrest and morphological alterations in mouse embryonic fibroblasts lacking RAS proteins

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月31日

查看全文
  • Isabel Fernández-Pisonero,
  • L. Francisco Lorenzo-Martín,
  • Mattias Drosten,
  • Eugenio Santos,
  • Mariano Barbacid,
  • Balbino Alarcón,
  • Xosé R. Bustelo

摘要

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.