4月12日，国际知名学术期刊《欧洲分子生物学学会会刊》（The EMBO Journal）在线发表了中科院上海生科院生化与细胞所刘小龙研究组的研究成果“LKB1 regulates TCR-mediated PLCg1 activation and thymocyte positive selection”。该工作揭示了丝氨酸/苏氨酸激酶LKB1调控T细胞抗原受体(TCR)信号转导和胸腺细胞阳性选择的分子机制。
胸腺细胞（前体T细胞）在胸腺中经历受体基因重排和阳性选择等重要的生物学过程，分化成熟为有功能的T细胞，然后迁移到外周淋巴器官行使其免疫功能。丝氨酸/苏氨酸激酶LKB1在调节细胞能量代谢平衡、调控胚胎血管生成、维持个体发育和抑制癌症发生等方面有着很重要的作用。此前，刘小龙研究组发现LKB1通过激活细胞能量感受器AMPK和上调抗凋亡因子Bcl-XL的表达，调控胸腺细胞存活（Cell Research，2010）。
最近该研究组的博士研究生曹永浩和李海等研究发现，LKB1还调控胸腺细胞的阳性选择。在免疫T细胞特异的LKB1敲除小鼠中，胸腺细胞不能够分化成熟为T细胞。他们的研究表明：TCR信号激活的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信号转导体(LAT signalosome)上，促进PLCγ1的磷酸化并激活Ca2+流，进而上调T细胞分化决定因子ThPOK和Runx3的转录表达，调控胸腺细胞阳性选择。而在Lkb1基因敲除的小鼠中，胸腺细胞的TCR信号转导受阻，胸腺细胞阳性选择停滞。该研究不仅揭示了LKB1调控胸腺细胞分化成熟的新功能，还发现LKB1能够响应并转导细胞外信号。
该研究工作得到国家自然科学基金委，科技部和上海市科委的经费支持。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
