Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression.
Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression.
复制标题
DOI：
10.1186/s12964-014-0071-9
复制
发表时间：
2014-11-14
期刊：
影响因子：
--
通讯作者：
Larose L
中科院分区：
文献类型：
--
作者：
Li H;Dusseault J;Larose L
PI 3 K/Akt通路的激活介导由受体酪氨酸激酶调节的关键细胞功能，如细胞生长、增殖、存活和代谢。先前，我们报道了全身敲除含Src同源结构域的衔接蛋白Nck 1改善了肥胖小鼠肝脏中的整体葡萄糖稳态和胰岛素诱导的PI 3 K/Akt通路的激活。本研究的目的是阐明Nck 1缺失调节肝脏胰岛素信号传导的机制。在这里，我们证明，Nck 1调节蛋白酪氨酸磷酸酶1B（PTP 1B）依赖性机制中的PI 3 K/Akt通路的激活。事实上，在HepG 2细胞中通过siRNA消耗Nck 1增强了PI 3 K依赖性基础和生长因子诱导的Akt活化。因此，从Nck 1 −/−小鼠分离的原代肝细胞也显示出对胰岛素应答的Akt活化增强。Nck 1缺失的HepG 2细胞中PI 3 K/Akt通路的激活依赖于较高水平的酪氨酸磷酸化蛋白，并与降低的PTP 1B水平相关。有趣的是，细胞中的Nck 1和PTP 1B存在于一个共同的分子复合物中，它们的相互作用依赖于Nck 1的SH 3结构域。最后，Nck 1在HepG 2细胞中的缺失既不影响PTP 1B基因的转录，也不影响PTP 1B蛋白的稳定性，这表明Nck 1在翻译水平上调节PTP 1B的表达。我们的研究提供了强有力的证据支持衔接蛋白Nck 1与PTP 1B相互作用，也调节PTP 1B的表达。以这种方式，Nck 1在调节PI 3 K/Akt通路中起作用。
Activation of the PI3K/Akt pathway mediates crucial cellular functions regulated by receptor tyrosine kinases, such as cell growth, proliferation, survival and metabolism. Previously, we reported that the whole-body knockout of the Src homology domain-containing adaptor protein Nck1 improves overall glucose homeostasis and insulin-induced activation of the PI3K/Akt pathway in liver of obese mice. The aim of the current study is to elucidate the mechanism by which Nck1 depletion regulates hepatic insulin signaling. Here, we demonstrate that Nck1 regulates the activation of the PI3K/Akt pathway in a protein tyrosine phosphatase 1B (PTP1B)-dependent mechanism. Indeed, depletion of Nck1 by siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation. In accordance, primary hepatocytes isolated from Nck1−/− mice also display enhanced Akt activation in response to insulin. Activation of the PI3K/Akt pathway in Nck1-depleted HepG2 cells relies on higher levels of tyrosine-phosphorylated proteins and correlates with decreased PTP1B levels. Interestingly, Nck1 and PTP1B in cells are found in a common molecular complex and their interaction is dependent on the SH3 domains of Nck1. Finally, Nck1 depletion in HepG2 cells neither affects PTP1B gene transcription nor PTP1B protein stability, suggesting that Nck1 modulates PTP1B expression at the translational level. Our study provides strong evidence supporting that the adaptor protein Nck1 interacts with PTP1B and also regulates PTP1B expression. In this manner, Nck1 plays a role in regulating the PI3K/Akt pathway.
登录
查看更多内容
影响因子：
7.7
作者：
Delibegovic M;Zimmer D;Kauffman C;Rak K;Hong EG;Cho YR;Kim JK;Kahn BB;Neel BG;Bence KK
通讯作者：
Bence KK
影响因子：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
DOI：
10.1152/ajpendo.00088.2010
发表时间：
2011-03-01
影响因子：
5.1
作者：
Latreille, Mathieu;Laberge, Marie-Kristine;Larose, Louise
通讯作者：
Larose, Louise
影响因子：
4.8
作者：
Clemens, JC;Ursuliak, Z;Dixon, JE
通讯作者：
Dixon, JE
影响因子：
4.8
作者：
Gu, F;Nguyên, DT;Chevet, E
通讯作者：
Chevet, E