Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima, 727-0023, Japan.
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-Minamimachi, Chuou-ku, Kobe, 650-0047, Japan.
Biochem Biophys Res Commun. 2022 Nov 5;628:91-97. doi: 10.1016/j.bbrc.2022.08.058. Epub 2022 Aug 30.
The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes. In this paper, we report an amino acid substitution mutation (K291R) in GAREM1, in a patient with idiopathic short stature, which indicates that the mutant exhibits dominant-negative properties. The GAREM K291R mutant did not promote Erk activation in EGF-stimulated cultured cells. Similar features were also observed in cells in which GAREM1 expression was suppressed by genome editing; along with Erk, phosphorylation of S6 kinase and 4EBP1, whose activation is necessary for cell proliferation and biological growth, were inhibited Furthermore, we generated mice deficient in GAREM1 and showed that the mutant mice are lighter in weight. Overall, the results of this paper suggest that GAREM1 is required for normal growth and for maintaing average body size in humans and mice.
衔接蛋白 GAREM 有两种亚型。在培养细胞中，每种亚型都参与细胞生长因子受体下游的 Erk 激活信号转导。关于它们在单个动物中的作用，我们之前报道过，大脑中高表达 GAREM2 的基因敲除小鼠表现出情绪变化。在本文中，我们报告了一名特发性身材矮小患者中存在 GAREM1 的氨基酸替换突变（K291R），表明该突变具有显性负性。GAREM K291R 突变体不能促进 EGF 刺激的培养细胞中的 Erk 激活。在通过基因组编辑抑制 GAREM1 表达的细胞中也观察到了类似的特征；与 Erk 一起，S6 激酶和 4EBP1 的磷酸化受到抑制，其激活对于细胞增殖和生物生长是必需的。此外，我们生成了 GAREM1 基因敲除小鼠，并表明突变小鼠体重较轻。总体而言，本文的结果表明，GAREM1 对于人类和小鼠的正常生长和维持平均体型是必需的。
