Clark James F, Soriano Philippe
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
bioRxiv. 2023 Mar 25:2023.03.23.534012. doi: 10.1101/2023.03.23.534012.
FGF activation is known to engage canonical signals, including ERK/MAPK and PI3K/AKT, through various effectors including FRS2 and GRB2. mutants that abrogate canonical intracellular signaling exhibit a range of mild phenotypes but are viable in contrast to embryonic lethal mutants. GRB2 has been reported to interact with FGFR2 through a non-traditional mechanism, by binding to the C-terminus of FGFR2 independently of FRS2 recruitment. To investigate if this interaction provides functionality beyond canonical signaling, we generated mutant mice harboring a C-terminal truncation (T). We found that mice are viable and have no distinguishable phenotype, indicating that GRB2 binding to the C-terminal end of FGFR2 is not required for development or adult homeostasis. We further introduced the mutation on the sensitized background but found that mutants did not exhibit significantly more severe phenotypes. We therefore conclude that, while GRB2 can bind to FGFR2 independently of FRS2, this binding does not have a critical role in development or homeostasis.
已知成纤维细胞生长因子（FGF）激活通过包括FRS2和GRB2在内的各种效应器参与经典信号传导，包括细胞外调节蛋白激酶/丝裂原活化蛋白激酶（ERK/MAPK）和磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）。消除经典细胞内信号传导的突变体表现出一系列轻度表型，但与胚胎致死突变体相比是存活的。据报道，GRB2通过一种非传统机制与成纤维细胞生长因子受体2（FGFR2）相互作用，即通过独立于FRS2募集而与FGFR2的C末端结合。为了研究这种相互作用是否提供了超出经典信号传导的功能，我们生成了携带C末端截短（T）的突变小鼠。我们发现T小鼠是存活的，并且没有可区分的表型，这表明GRB2与FGFR2的C末端结合对于发育或成年期稳态不是必需的。我们进一步在敏感背景上引入T突变，但发现T突变体没有表现出明显更严重的表型。因此，我们得出结论，虽然GRB2可以独立于FRS2与FGFR2结合，但这种结合在发育或稳态中没有关键作用。
