GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling.
GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling.
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DOI：
10.1002/jcp.24090
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发表时间：
2012-12
影响因子：
5.6
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Pfaffenbach, Kyle T.;Pong, Michelle;Morgan, Todd E.;Wang, Hongjun;Ott, Kate;Zhou, Beiyun;Longo, Valter D.;Lee, Amy S.
葡萄糖调节蛋白78/免疫球蛋白结合蛋白（GRP 78/BiP）是一种ER伴侣蛋白，是未折叠蛋白反应（UPR）的主要调节因子。GRP 78对明显诱导的ER应激的反应已经很好地建立，而GRP 78对生理变化的调节则较少被表征。在这项研究中，我们研究了GRP 78对IGF-1生长因子信号传导减少的调节，这是热量限制（CR）的常见结果。ER伴侣蛋白表达在从热量限制（CR）和随意喂养的小鼠的肝脏制备的细胞裂解物中定量，以及在正常培养基或血清饥饿中生长的MEF。使用IGF-1受体过表达（R+）或缺失（R-）的MEFs研究了IGF-1信号对GRP 78表达的需求，并使用mTORC 1和PI 3 K抑制剂以及与shRNA对照相比敲减转录因子FOXO 1的R-细胞检查了调节机制。我们观察到CR小鼠和血清饥饿的MEF细胞中GRP 78蛋白表达减少了40%。R-细胞的AKT磷酸化水平显著降低，ER分子伴侣水平降低，特别是GRP 78减少了80%。尽管GRP 78表达减少了80%，但R−细胞并没有处于慢性ER应激下，而是完全能够激活未折叠蛋白反应（UPR）。在R−细胞中，FOXO 1-AAA的强制表达和FOXO 1的敲低都不会影响GRP 78的表达。总之，我们报告说，IGF-1受体信号调节GRP 78的表达，通过PI 3 K/AKT/mTORC 1轴独立于典型的UPR和FOXO 1。
Glucose regulated protein 78/immunoglobulin binding protein (GRP78/BiP) is an ER chaperone protein and master regulator of the unfolded protein response (UPR). The response of GRP78 to overt pharmacologically induced ER stress is well established, whereas the modulation of GRP78 to physiologic changes is less characterized. In this study, we examined the regulation of GRP78 in response to reduced IGF-1 growth factor signaling, a common consequence of calorie restriction (CR). ER chaperone protein expression was quantified in cell lysates prepared from the livers of calorie restricted (CR) and ad libitum fed mice, as well as MEFs grown in normal medium or serum starved. The requirement of IGF-1 signaling on GRP78 expression was studied using MEFs with IGF-1 receptor overexpression (R+) or deletion (R−), and the regulatory mechanism was examined using mTORC1 and PI3K inhibitors, as well as R− cells with knockdown of transcription factor FOXO1 compared to shRNA control. We observed a 40% reduction in GRP78 protein expression in CR mice and in serum-starved MEF cells. R− cells had drastically reduced AKT phosphorylation and exhibited lower levels of ER chaperones, in particular 80% less GRP78. Despite an 80% reduction in GRP78 expression, R− cells were not under chronic ER stress, but were fully capable of activating the unfolded protein response (UPR). Neither forced expression of FOXO1-AAA nor knockdown of FOXO1 in R− cells affected GRP78 expression. In conclusion, we report that IGF-1 receptor signaling regulates GRP78 expression via the PI3K/AKT/mTORC1 axis independent of the canonical UPR and FOXO1.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
5.3
作者：
Baumeister, P;Luo, SZ;Lee, AS
通讯作者：
Lee, AS
影响因子：
11.5
作者：
Chitnis, Meenali M.;Yuen, John S. P.;Macaulay, Valentine M.
通讯作者：
Macaulay, Valentine M.
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
DOI：
10.1073/pnas.0807691105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Fu, Yong;Wey, Shiuan;Lee, Amy S.
通讯作者：
Lee, Amy S.