4月12日，國(guó)際知名學(xué)術(shù)期刊《歐洲分子生物學(xué)學(xué)會(huì)會(huì)刊》（The EMBO Journal）在線發(fā)表了中科院上海生科院生化與細(xì)胞所劉小龍研究組的研究成果“LKB1 regulates TCR-mediated PLCg1 activation and thymocyte positive selection”,。該工作揭示了絲氨酸/蘇氨酸激酶LKB1調(diào)控T細(xì)胞抗原受體(TCR)信號(hào)轉(zhuǎn)導(dǎo)和胸腺細(xì)胞陽(yáng)性選擇的分子機(jī)制,。
胸腺細(xì)胞（前體T細(xì)胞）在胸腺中經(jīng)歷受體基因重排和陽(yáng)性選擇等重要的生物學(xué)過程，分化成熟為有功能的T細(xì)胞,，然后遷移到外周淋巴器官行使其免疫功能,。絲氨酸/蘇氨酸激酶LKB1在調(diào)節(jié)細(xì)胞能量代謝平衡、調(diào)控胚胎血管生成,、維持個(gè)體發(fā)育和抑制癌癥發(fā)生等方面有著很重要的作用,。此前，劉小龍研究組發(fā)現(xiàn)LKB1通過激活細(xì)胞能量感受器AMPK和上調(diào)抗凋亡因子Bcl-XL的表達(dá),，調(diào)控胸腺細(xì)胞存活（Cell Research,，2010）。
最近該研究組的博士研究生曹永浩和李海等研究發(fā)現(xiàn),，LKB1還調(diào)控胸腺細(xì)胞的陽(yáng)性選擇,。在免疫T細(xì)胞特異的LKB1敲除小鼠中，胸腺細(xì)胞不能夠分化成熟為T細(xì)胞,。他們的研究表明：TCR信號(hào)激活的Lck直接磷酸化LKB1蛋白36,、261和365位的酪氨酸，磷酸化的LKB1招募PLCγ1到LAT信號(hào)轉(zhuǎn)導(dǎo)體(LAT signalosome)上,，促進(jìn)PLCγ1的磷酸化并激活Ca2+流,，進(jìn)而上調(diào)T細(xì)胞分化決定因子ThPOK和Runx3的轉(zhuǎn)錄表達(dá)，調(diào)控胸腺細(xì)胞陽(yáng)性選擇,。而在Lkb1基因敲除的小鼠中,，胸腺細(xì)胞的TCR信號(hào)轉(zhuǎn)導(dǎo)受阻，胸腺細(xì)胞陽(yáng)性選擇停滯,。該研究不僅揭示了LKB1調(diào)控胸腺細(xì)胞分化成熟的新功能,，還發(fā)現(xiàn)LKB1能夠響應(yīng)并轉(zhuǎn)導(dǎo)細(xì)胞外信號(hào)。
該研究工作得到國(guó)家自然科學(xué)基金委,，科技部和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
The EMBO Journal , (12 April 2011) | doi:10.1038/emboj.2011.116
LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte positive selection
Yonghao Cao, Hai Li, Haifeng Liu, Min Zhang, Zichun Hua, Hongbin Ji and Xiaolong Liu
Abstract
The serine/threonine kinase LKB1 is a tumour suppressor that regulates cell growth, polarity, and proliferation in many different cell types. We previously demonstrated that LKB1 controls thymocyte survival via regulation of AMPK activation. In this study, we show that LKB1 was also involved in thymocyte positive selection through regulation of T cell receptor (TCR) signalling. Both Lck-Cre- and CD4-Cre-mediated deletion of LKB1 impaired the generation of mature CD4 and CD8 single positive (SP) thymocytes that might have resulted from the attenuated tyrosine phosphorylation of phospholipase C-γ 1 (PLCγ1) in the absence of LKB1. We found that LKB1 was directly phosphorylated by Lck at tyrosine residues 36, 261, and 365 and predominately interacted with LAT and PLCγ1 following TCR stimulation. Loss of LKB1 led to impaired recruitment of PLCγ1 to the LAT signalosome. Correlatively, LKB1-deficient thymocytes failed to upregulate lineage-specifying factors, and to differentiate into SP thymocytes even if their impaired survival was rescued. These observations indicated that LKB1 is a critical component involved in TCR signalling, and our studies provide novel insights into the mechanisms of LKB1-mediated thymocyte development.
