Grb2与AMPK、TSC2的相互作用及其在细胞生长调控中的功能研究
摘要
Grb2 (growth factor receptor-bound protein-2)是一个转接蛋白(adaptor protein),它主要连接上游的受体激酶和下游的磷酸化底物,介导激酶对底物的磷酸化,在整个信号转导通路中是不可或缺的。AMPK (AMP-activated protein kinase)属于哺乳动物中高度保守的丝氨酸／苏氨酸蛋白激酶,是一个异源三聚体蛋白,由α、β和γ3种亚基组成。AMPK感受剧烈运动、饥饿、缺血、缺氧及代谢等因素,在调节能量代谢的信号转导机制中起着非常重要的枢纽作用。TS (Tuberous sclerosis)是一种结节性硬化综合症,由TSC1和TSC2基因突变引起的。TSC2表达的蛋白产物又称为tuberin,是一个肿瘤抑制因子,在RTK-PI3K-Akt-TSC1/TSC2-mTOR的信号转导通路中通过抑制mTOR的活性,控制细胞的大小与分化。本实验室自2002年起参与人类肝脏蛋白质组计划以来,对肝脏信号转导通路网络展开深入的研究,拟揭示以肝脏为主体的信号分子连锁图和定位图。其中,我们从Ras-MAPK和P13K-Akt两条通路出发,以Grb2为核心诱饵,用酵母双杂交体系对肝脏文库进行大规模筛选,发现两种与Grb2相互作用的候补蛋白：AMPKβ1与TSC2。在过表达的情况下通过免疫共沉淀实验验证了Grb2能够与AMPKβ1相互作用,且在内源性表达时,这种相互作用也是真实存在的。而且进一步确证了Grb2的SH2结构域与AMPKβ1的KIS结构域是两分子相互作用的结合区域。另外,利用间接免疫荧光观察到过表达及内源性Grb2与AMPK共定位在细胞质中。由于已知AMPK与TSC2是存在相互作用的,因此我们推测Grb2、AMPK及TSC2是线性的复合体关系。进一步研究发现,Grb2能够调控AMPK的磷酸化水平,通过RNAi敲低Grb2后,AMPKThr172位点的磷酸化水平迅速降低。这提示AMPK的活性也受到抑制,进而可能影响了AMPK与TSC2的功能关系,也进一步降低了AMPK对TSC2的磷酸化调控水平,抑制了TSC2的活性,间接增加了mTOR的活性,促进了细胞的生长与增值。值得一提的是,过表达的TSC2能够促使Grb2从细胞质向细胞核转移,机制尚不明确。另外,JAB1与CKIP-1也能够与AMPK相互作用。本研究揭示了一条由Grb2、AMPK、TSC2、mTOR组成的调控蛋白质合成进而调控细胞生长的新途径。
Growth factor receptor-bound protein 2 (Grb2) is an extensively studied adaptor protein involved in cell signaling. Grb2 connects with up stream protein kinases and down stream phosphorylation targets, and plays a very significant role in the growth factor receptor signaling transduction passway. The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. AMPK is part of Ser/Thr protein kinase, and composed of a,βand y three subunits. Once activated, AMPK switches on catabolic pathways, as well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level. Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. TSC2 is a tumor suppressor and control cell size and differentiation by restrain mTOR activation in RTK-PI3K-Akt-TSC1/TSC2-mTOR signaling transduction passway. Since our lab participated in the Human Liver Proteome Plan in 2002, we have done further reaserch on complex net of liver signal transduction pathway, in hope of revealing the Signaling Molecular Linkage Map and Localization Map, which taking the liver as the main part. Our research carried on through the pathway of Ras-MAPK and PI3K-Akt, and taking Grb2 as bait to select the Liver Library on a large scale using the yeast two-hybrid system. Two alternative protein that may interact with Grb2 were selected,which are AMPKβ1 and TSC2. We report that Grb2 can interacte with AMPKβ1. Furthermore, Grb2 SH2 domain and AMPK KIS domain are interaction regions. In addition, Grb2 and AMPK colocalize in cytoplasm by indirect immune fluorescence. Advanced study, that Grb2 can regulate AMPK phosphorylation. Grb2 RNA interference could reduce AMPK Thr172 phosphorylation and suppress TSC2 activation, indirectly increase mTOR activation, accelerate cell growth and proliferation. Noticeably, overexpressed TSC2 could promote Grb2 transfer from cytoplasm to nucleus. Moreover, we also found that JAB1 and CKIP-1 could interact with AMPK. We report a new regulating protein synthesis and cell growth passway which composed of Grb2, AMPK, TSC2 and mTOR.
Growth factor receptor-bound protein 2 (Grb2) is an extensively studied adaptor protein involved in cell signaling. Grb2 connects with up stream protein kinases and down stream phosphorylation targets, and plays a very significant role in the growth factor receptor signaling transduction passway. The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. AMPK is part of Ser/Thr protein kinase, and composed of a,βand y three subunits. Once activated, AMPK switches on catabolic pathways, as well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level. Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. TSC2 is a tumor suppressor and control cell size and differentiation by restrain mTOR activation in RTK-PI3K-Akt-TSC1/TSC2-mTOR signaling transduction passway. Since our lab participated in the Human Liver Proteome Plan in 2002, we have done further reaserch on complex net of liver signal transduction pathway, in hope of revealing the Signaling Molecular Linkage Map and Localization Map, which taking the liver as the main part. Our research carried on through the pathway of Ras-MAPK and PI3K-Akt, and taking Grb2 as bait to select the Liver Library on a large scale using the yeast two-hybrid system. Two alternative protein that may interact with Grb2 were selected,which are AMPKβ1 and TSC2. We report that Grb2 can interacte with AMPKβ1. Furthermore, Grb2 SH2 domain and AMPK KIS domain are interaction regions. In addition, Grb2 and AMPK colocalize in cytoplasm by indirect immune fluorescence. Advanced study, that Grb2 can regulate AMPK phosphorylation. Grb2 RNA interference could reduce AMPK Thr172 phosphorylation and suppress TSC2 activation, indirectly increase mTOR activation, accelerate cell growth and proliferation. Noticeably, overexpressed TSC2 could promote Grb2 transfer from cytoplasm to nucleus. Moreover, we also found that JAB1 and CKIP-1 could interact with AMPK. We report a new regulating protein synthesis and cell growth passway which composed of Grb2, AMPK, TSC2 and mTOR.
引文
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