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 是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因子。因此，GRP78 在高度增殖的细胞中经常上调，以应对蛋白质合成和代谢压力升高。IGF-1 是细胞生长、代谢和存活的有效调节剂。以前我们通过利用小鼠胚胎成纤维细胞模型系统发现 GRP78 是 IGF-1 信号传导的新下游靶标，其中 IGF-1 受体 (IGF-1R) 过表达 (R+) 或敲除 (R-)。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 导致 GRP78 和转录因子 ATF4 同时减少。