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李林
研究员,中科院院士,上海生科院院长,所学术委员会主任,分子生物学国家重点实验室主任
E-mail: lli@@sibs.ac.cn


个人简介

1983年毕业于南京大学生物系生物化学专业获学士学位,1989年在中国科学院上海生物化学研究所研究生毕业获博士学位,1990至1992年在美国纽约州立大学石溪分校生理与生物物理系做博士后研究,1992年回上海生化所工作至今。1991年被上海生化所聘为副研究员,1993年晋升为研究员,2011年被增选为中国科学院院士。2000年至2005年担任生物化学与细胞生物学研究所(生化与细胞所)学术委员会主任,2002至2004年担任生化与细胞所常务副所长,2004至2009年担任所长,2008至2013年担任中国科学院上海生命科学研究院副院长,2013年至今担任院长。此外, 2006年至今担任分子生物学国家重点实验室主任,2011年至今再次担任生化与细胞所学术委员会主任。1995年获得国家杰出青年科学基金的资助,1996年获香港求是基金会“杰出青年学者奖”。1999至2003年主持国家自然科学基金重大项目“蛋白质组及蛋白质结构动态变化与功能关系”,2002至2008年作为首席科学家主持国家重点基础研究发展规划 (973计划)“炎症的细胞信号转导网络及其调控机制”项目,2010至2014年作为首席科学家主持国家重大科学研究计划“细胞生长调控的重要蛋白质群的功能与作用机制”项目,2006至2011年作为学术带头人主持国家基金委创新群体“细胞命运决定的分子网络”项目。目前担任中国生物化学与分子生物学会理事长。2008至2013担任《JBC》编委,目前担任《Cell Research》、《Cell Discovery》、《JMCB》、《ABBS》等期刊编委或编辑等。 


研究方向

细胞信号转导与调控的分子机制与功能


研究工作

        总体上,我们实验室通过研究Wnt信号转导的蛋白质相互作用网络及其调控的分子机制,着眼于新分子、新机制及新功能的发现,以期更深入了解胚胎发育、癌症发生等过程中Wnt信号所发挥的生物学功能。

        Wnt信号转导通路是一类高度保守的信号转导通路,在动物体早期发育中决定背腹轴形成、胚层建立、体节分化、组织或器官形成等一系列重要事件,并直接控制增殖、分化、极化、凋亡与抗凋亡等细胞命运;且与肿瘤发生密切相关。我们实验室的研究工作围绕Wnt信号转导通路展开,在多个层面和系统中力求阐明Wnt信号通路的分子机制及相关的生物学功能。

        在分子机制研究层面,将综合应用生物化学与分子生物学、细胞生物学、发育生物学、结构生物学、及化学生物学等多种研究技术方法,研究目标蛋白质及相关复合物成员之间的相互作用关系、聚集状态、修饰、定位、及蛋白质关键位点等等,以此为切入点,揭示Wnt信号转导调控的新机制。同时,结合蛋白质组学等规模化的组学手段,高通量筛选参与Wnt信号传递的新分子、新修饰及新位点,为机制研究提供更多线索。目前的工作主要包括Wnt信号膜质传递、细胞核内转录复合物调控、b-catenin入核机制等几方面,我们的工作已经或将为这些环节的机制揭示取得突破性的进展。

        基于Wnt信号重要的生物学功能,我们另一方面的工作是在模式生物系统中探索和验证Wnt信号转导通路的新功能。我们已经建立斑马鱼模式生物系统,除了常规的显微注射mRNA或MO和原位杂交外,还新建了不同的基因突变或者转基因品系,来鉴定我们研究的新分子、新机制在斑马鱼胚胎发育中所起到的作用;另一方面,我们已经建立了多个参与Wnt信号新分子的基因敲除小鼠,同时借助将这些基因敲除小鼠与axin2-RFP小鼠进行杂交繁育,建立一个荧光直观检测Wnt信号靶基因axin2表达水平的系统,不仅可以发现Wnt信号在小鼠胚胎发育时期发挥作用的新线索,也可以检测研究目标基因是否在一些尚未发现的发育过程或环节具有新的功能。

        Wnt信号通路的失调与肿瘤发生密切相关。我们开展了大规模基于Wnt信号活性调节的小分子化合物的筛选,寻找和鉴定显著影响Wnt信号通路活性的小分子,并对其调控Wnt信号的靶点机制展开深入研究,使其成为Wnt信号机制与功能研究的工具药,或者可能为肿瘤及其它疾病治疗提供新的作用靶点和潜在的先导化合物。


代表性论文

  1. Chao Wang, Wenxiang Zhang, Meng-Xin Yin, Lianxin Hu, Peixue Li, Jiajun Xu, Hongling Huang, Shimin Wang, Yi Lu, Wenqing Wu, Margaret S. Ho, Lin Li, Yun Zhao, and Lei Zhang* (2015) Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis. Nature Communications, in press.
  2. Jia Shen, Xiangpeng Sheng, ZeNan Chang, Qian Wu, Sheng Wang, Zongliang Xuan, Dan Li, Yalan Wu, Yongjia Shang, Xiangtao Kong, Long Yu, Lin Li, Kangchen Ruan, Hongyu Hu, Ying Huang, Lijian Hui, Dong Xie, Fudi Wang, and Ronggui Hu* (2014) Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Reports, 7, 1-14.
  3. Zhengzhao Liu, Peng Chen, Hong Gao, Yu Gu, Jiao Yang, Hong Peng, Xingxing Xu, Haifeng Wang, Meiqiang Yang, Xiaoying Liu, Libin Fan, Shiyao Chen, Jian Zhou, Yihong Sun, Kangchen Ruan, Shuqun Cheng, Masaaki Komatsu, Eileen White, Lin Li, Hongbin Ji, Daniel Finley, Ronggui Hu* (2014) Ubiquitylation of autophagy receptor optineurin. Cancer Cell, 26, 106-120.
  4. Xiaomin Song, Sheng Wang, and Lin Li* (2014) New insights into the regulation of Axin function in canonical Wnt signaling pathway. Protein & Cell, 5, 186-193
  5. Ying-ying Jia, Fen Nie, Ai-ying Du, Zhang-cheng Chen, Yuan-bo Qin, Tao Huang, Xiao-min Song, and Lin Li* (2014) Thymine DNA glycosylase promotes transactivation of b-catenin/TCFs by cooperating with CBP. J. Mol. Cell Biol., 6, 231-239
  6. Haofei Miao, Yingying Jia, Sichun Xie, Xin Wang, Jianfei Zhao, Youjun Chu, Zhilei Zhou, Zhubing Shi, Xiaomin Song*, and Lin Li* (2014) Structural insights into the C1q domain of Caprin-2 in canonical Wnt signaling. J. Biol. Chem., 289, 34104–34113
  7. Cong Fei*, Xiaoli He, Sichun Xie, Haofei Miao, Zhilei Zhou, and Lin Li* (2014) Smurf1-mediated Axin ubiquitination requires Smurf1 C2 domain and is cell-cycle dependent. J. Biol. Chem., 289, 14170-14177
  8. Sheng Wang, Junlin Yin, Duozhi Chen, Fen Nie, Xiaomin Song, Cong Fei, Haofei Miao, Changbin Jing, Wenjing Ma, Lei Wang, Sichun Xie, Chen Li, Rong Zeng, Weijun Pan, Xiaojiang Hao*, and Lin Li* (2013) Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction. Nature Chem. Biol., 9, 579-585.
  9. Chun-Xiao Song, Keith E. Szulwach, Qing Dai, Ye Fu, Shi-Qing Mao, Li Lin, Craig Street, Yujing Li, Mickael Poidevin, Hao Wu, Juan Gao, Peng Liu, Lin Li, Guo-Liang Xu, Peng Jin, and Chuan He (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell, 153, 678-691.
  10. Cong Fei, Zhenfei Li, Chen Li, Yuelei Chen, Zhangcheng Chen, Xiaoli He, Li Mao, Xin Wang, Rong Zeng, and Lin Li* (2013) Smurf1-mediated Lys29-linked non-proteolytic poly-ubiquitination of Axin negatively regulates Wnt/β-catenin signaling. Mol. Cell Biol., 33, 4095-4105.
  11. Wei Wei, Meng Li, Jiyong Wang, Fen Nie and Lin Li* (2012) The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein. Mol. Cell Biol., 32, 3903-3912.
  12. Yu-Fei He, Bin-Zhong Li, Zheng Li, Peng Liu, Yang Wang, Qingyu Tang, Jianping Ding, Yingying Jia, Zhangcheng Chen, Lin Li, Yan Sun, Xiuxue Li, Qing Dai, Chun-Xiao Song, Kangling Zhang, Chuan He, and Guo-Liang Xu (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science, 333, 1303-1307.
  13. Tao Huang, Zhihui Xie, Jiyong Wang, Meng Li, Naihe Jing, and Lin Li* (2011) Nuclear Factor of Activated T Cell (NFAT) Proteins repress canonical Wnt signaling via its interaction with dishevelled (Dvl) protein and participate in regulating neural progenitor cell proliferation and differentiation. J. Biol. Chem., 286, 37399-37405.
  14. Wenwen Tang, Yong Zhang, Wenwen Xu, T. Kendall Harden, John Sondek, Le Sun, Lin Li, and Dianqing Wu* (2011) A PLCb/PI3Kg-GSK3 signaling pathway regulates cofilin phosphatase Slingshot2 and neutrophil polarization and chemotaxis. Dev. Cell, 21, 1038-1050.
  15. Zhihui Xie, Yongfeng Chen, Zhenfei Li, Ge Bai, Yue Zhu, Rui Yan, Fangzhi Tan, Ye-Guang Chen, Francois Guillemot, Lin Li, and Naihe Jing (2011) Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/b-catenin pathway. Proc. Natl. Acad. Sci. USA, 108, 12119-12124.
  16. Zhenfei Li, Fen Nie, Sheng Wang, and Lin Li* (2011) Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc. Natl. Acad. Sci. USA, 108, 3116-3123.
  17. Wei Wang, Haiyang Liu, Sheng Wang, Xiaojiang Hao*, and Lin Li* (2011) A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/b-catenin signaling and colon cancer cell tumorigenesis. Cell Res., 21, 730-740.
  18. Meng Li, He Wang, Tao Huang, Jiyong Wang, Yu Ding, Zhenfei Li, Jinkuo Zhang, and Lin Li* (2010) TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling. J. Biol. Chem., 285, 13397-13404.
  19. Ning Deng, Yanger Ye, Wei Wang, and Lin Li* (2010) Dishevelled interacts with p65 and acts as a repressor of NF-kB-mediated transcription. Cell Res., 20, 1117-1127.
  20. Bianhong Zhang, Meng Li, Liang Chen, Kai Yang, Yufei Shan, Lianhui Zhu, Shaogang Sun, and Lin Li*, and Chen Wang* (2009) The TAK1-JNK cascade is required for IRF3 function in the innate immune response. Cell Res., 19, 412-428.
  21. Ting Chen, Meng Li, Yu Ding, Leshuai Zhang, Ying Xi, Weijun Pan, Donglei Tao, Jiyong Wang, and Lin Li* (2009) Identification of zinc-finger bed domain containing 3 (ZBED3) as a novel axin-interacting protein that activates Wnt/b-catenin signaling. J. Biol. Chem., 284, 6683-6689.
  22. Weijun Pan, Sun-Cheol Choi, He Wang, Yuanbo Qin, Laura Volpicelli-Daley, Laura Swan, Louise Lucast, Cynthia Khoo, Xiaowu Zhang, Lin Li, Charles S. Abrams, Sergei Y. Sokol, and Dianqing Wu (2008) Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation. Science, 321, 1350-1353.
  23. Yu Ding, Ying Xi, Ting Chen, Ji-yong Wang, Dong-lei Tao, Zhi-li Wu, Yi-ping Li, Chen Li, Rong Zeng, and Lin Li* (2008) Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation. J. Cell Biol., 182, 865-872.
  24. Xiao-qing Gan, Ji-yong Wang, Ying Xi, Zhi-li Wu, Yi-ping Li, and Lin Li* (2008) Nuclear Dvl, c-Jun, b-catenin and TCF form a complex leading to stabilization of b-catenin/TCF interaction. J. Cell Biol., 180, 1087-1100.
  25. Weijun Pan, Yingying Jia, Tao Huang, Jiyong Wang, Donglei Tao, Xiaoqing Gan, and Lin Li* (2006) b-Catenin relieves I-mfa-mediated suppression of LEF-1 in mammalian cells. J. Cell Sci., 119, 4850-4856.
  26. Weijun Pan, Yingying Jia, Jiyong Wang, Donglei Tao, Xiaoqing Gan, Leonidas Tsiokas, Naihe Jing, Dianqing Wu, and Lin Li* (2005) b-Catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in P19 cells. Proc. Natl. Acad. Sci. USA, 102, 17378-17383.  
  27. Zhong Li, Xiemei Dong, Zhenglong Wang, Wenzhong Liu, Ning Deng, Yu Ding, Liuya Tang, Tim Hla, Rong Zeng, Lin Li*, and Dianqing Wu* (2005) Regulation of PTEN by Rho small GTPases. Nature Cell Biol., 7, 399-407. 
  28. Xiaoqing Gan, Zhihai Ma, Ning Deng, Jiyong Wang, Jianping Ding, and Lin Li* (2004) Involvement of the C-terminal proline-rich motif of G protein coupled receptor kinases in recognition of activated rhodopsin. J. Biol. Chem., 279, 49741-49746.
  29. Weijun Pan, Shuzhao Pang, Tao Huang, Huiyun Guo, Dianqing Wu, and Lin Li* (2004) Characterization of function of three domains in dishevelled-1: DEP domain is responsible for membrane translocation of dishevelled-1. Cell Res., 14, 324-330.
  30. Lin Li*, Junhao Mao, Le Sun, Wenzhong Liu & Dianqing Wu* (2002) Second cysteine-rich domain of dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J. Biol. Chem., 277, 5977-5981.
  31. Junhao Mao, Jiyong Wang, Bo Liu, Weijun Pan, Gist H. Farr III, Christopher Flint, Huidong Yuan, Shinji Takada, David Kimelman, Lin Li* & Dianqing Wu* (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. Cell, 7, 801-809.
  32. Qi-heng Yang, Zheng Zhu, Meng-qiu Dong, Song Ling, Chun-lai Wu & Lin Li* (2001) Binding of ATP to the fructose-2,6-bisphosphatase domain of chicken liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase leads to activation of its 6-phosphofructo-2-kinase. J. Biol. Chem., 276, 24608-24613.
  33. Xiao-qing Gan, Ji-yong Wang, Qi-heng Yang, Zhong Li, Feng Liu, Gang Pei & Lin Li* (2000) Interaction between the conserved region in the C-terminal domain of grk2 and rhodopsin is necessary for grk2 to catalyze receptor phosphorylation. J. Biol. Chem., 275, 8469-8474.

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