Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Cell Signal. 2020 Nov;75:109736. doi: 10.1016/j.cellsig.2020.109736. Epub 2020 Aug 14.
GRP78, a major molecular chaperone, is critical for the folding and maturation of membrane and secretory proteins and serves as the master regulator of the unfolded protein response. Thus, GRP78 is frequently upregulated in highly proliferative cells to cope with elevated protein synthesis and metabolic stress. IGF-1 is a potent regulator of cell growth, metabolism and survival. Previously we discovered that GRP78 is a novel downstream target of IGF-1 signaling by utilizing mouse embryonic fibroblast model systems where the IGF-1 receptor (IGF-1R) was either overexpressed (R+) or knockout (R-). Here we investigated the mechanisms whereby GRP78 is upregulated in the R+ cells. Our studies revealed that suppression of PI3K/AKT/mTOR downstream of IGF-1R signaling resulted in concurrent decrease in GRP78 and the transcription factor ATF4. Through knock-down and overexpression studies, we established ATF4 as the essential downstream nodal of the PI3K/AKT/mTOR signaling pathway critical for GRP78 transcriptional upregulation mediated by IGF-1R.
GRP78，一种主要的分子伴侣，对于膜和分泌蛋白的折叠和成熟至关重要，并且是未折叠蛋白反应的主要调节剂。因此，GRP78 在高度增殖的细胞中经常上调，以应对升高的蛋白质合成和代谢应激。IGF-1 是细胞生长、代谢和存活的有力调节剂。之前，我们通过利用 IGF-1 受体（IGF-1R）过表达（R+）或敲除（R-）的小鼠胚胎成纤维细胞模型系统，发现 GRP78 是 IGF-1 信号的一种新型下游靶标。在这里，我们研究了 GRP78 在 R+细胞中上调的机制。我们的研究表明，抑制 IGF-1R 信号下游的 PI3K/AKT/mTOR 会导致 GRP78 和转录因子 ATF4 的同时减少。通过敲低和过表达研究，我们确定 ATF4 是 PI3K/AKT/mTOR 信号通路的关键下游节点，对于由 IGF-1R 介导的 GRP78 转录上调至关重要。
