Insulin-like growth factor 1 (IGF-1) enhances the protein expression of CFTR.
Insulin-like growth factor 1 (IGF-1) enhances the protein expression of CFTR.
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DOI：
10.1371/journal.pone.0059992
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Guggino WB
中科院分区：
文献类型：
--
作者：
Lee HW;Cheng J;Kovbasnjuk O;Donowitz M;Guggino WB
在囊性纤维化（CF）患者的血清中观察到低水平的胰岛素样生长因子1（IGF-1）。然而，低血清IGF-1对囊性纤维化跨膜传导调节因子（CFTR）的影响尚未研究，CFTR的功能缺陷是囊性纤维化的主要原因。在这里，我们表明在人类细胞中，IGF-1增加了稳态水平的成熟野生型CFTR的CFTR相关配体（CAL）和TC 10依赖的方式;此外，IGF-1增加CFTR介导的氯离子转运。使用受体光漂白荧光共振能量转移（FRET）测定，我们已经证实了CAL和CFTR在高尔基体的结合。我们还表明，CAL过表达抑制毛喉素诱导的CFTR的细胞表面表达的增加。我们发现IGF-1激活TC 10，而活性TC 10改变CAL和CFTR之间的功能关联。此外，IGF-1和活性TC 10可以逆转CAL介导的CFTR细胞表面表达的减少。IGF-1不增加ΔF508 CFTR的表达，其加工在ER中被阻止。这一发现与我们的观察结果一致，即IGF-1改变了高尔基体中CAL和CFTR的功能相互作用。然而，当用低温或校正剂VRT-325拯救ΔF508 CFTR并进入高尔基体时，IGF-1可以增加拯救的ΔF508 CFTR的表达。我们的数据支持一个模型，表明CAL-CFTR结合在高尔基体抑制CFTR运输到细胞表面，导致CFTR的降解途径，而不是。IGF-1激活的TC 10改变CFTR和CAL的相互作用，使CFTR进入质膜。这些发现提供了一种潜在的策略，使用IGF-1和校正剂的组合治疗来增加携带ΔF508突变的囊性纤维化患者中CFTR的高尔基体后表达。
Low levels of insulin-like growth factor 1 (IGF-1) have been observed in the serum of cystic fibrosis (CF) patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR), whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL)- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET) assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.
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影响因子：
15.9
作者：
DENNING, GM;OSTEDGAARD, LS;WELSH, MJ
通讯作者：
WELSH, MJ
DOI：
10.1523/jneurosci.3907-09.2009
发表时间：
2009-10-21
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dupraz S;Grassi D;Bernis ME;Sosa L;Bisbal M;Gastaldi L;Jausoro I;Cáceres A;Pfenninger KH;Quiroga S
通讯作者：
Quiroga S
影响因子：
64.5
作者：
Gee, Heon Yung;Noh, Shin Hye;Lee, Min Goo
通讯作者：
Lee, Min Goo
影响因子：
4.8
作者：
Chen, J;Wu, A;Baserga, R
通讯作者：
Baserga, R
影响因子：
5.1
作者：
Bruscia, E;Sangiuolo, F;Gruenert, DC
通讯作者：
Gruenert, DC