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人才隊伍

李林
研究員，中科院院士，所學術委員會主任
E-mail: lli@@sibs.ac.cn
實驗室主頁:

個人簡介：

　　1983年畢業(yè)于南京大學生物系生物化學專業(yè)獲學士學位，1989年在中國科學院上海生物化學研究所研究生畢業(yè)獲博士學位，1990至1992年在美國紐約州立大學石溪分校生理與生物物理系做博士后研究，1992年回上海生化所工作至今。1991年被上海生化所聘為副研究員，1993年晉升為研究員，2011年被增選為中國科學院院士。2000年至2005年擔任生物化學與細胞生物學研究所(生化與細胞所)學術委員會主任，2002至2004年擔任生化與細胞所常務副所長，2004至2009年擔任所長，2008至2013年擔任中國科學院上海生命科學研究院副院長，2013年至今擔任院長。此外， 2006年至今擔任分子生物學國家重點實驗室主任，2011年至今再次擔任生化與細胞所學術委員會主任。1995年獲得國家杰出青年科學基金的資助，1996年獲香港求是基金會“杰出青年學者獎”。1999至2003年主持國家自然科學基金重大項目“蛋白質組及蛋白質結構動態(tài)變化與功能關系”，2002至2008年作為首席科學家主持國家重點基礎研究發(fā)展規(guī)劃 (973計劃)“炎癥的細胞信號轉導網絡及其調控機制”項目，2010至2014年作為首席科學家主持國家重大科學研究計劃“細胞生長調控的重要蛋白質群的功能與作用機制”項目，2006至2011年作為學術帶頭人主持國家基金委創(chuàng)新群體“細胞命運決定的分子網絡”項目。目前擔任中國生物化學與分子生物學會理事長。2008至2013擔任《JBC》編委，目前擔任《Cell Research》、《Cell Discovery》、《JMCB》、《ABBS》等期刊編委或編輯等。

社會任職：

研究方向：

細胞信號轉導與調控的分子機制與功能

研究工作：

　　總體上，我們實驗室通過研究Wnt信號轉導的蛋白質相互作用網絡及其調控的分子機制，著眼于新分子、新機制及新功能的發(fā)現，以期更深入了解胚胎發(fā)育、癌癥發(fā)生等過程中Wnt信號所發(fā)揮的生物學功能。

　　Wnt信號轉導通路是一類高度保守的信號轉導通路，在動物體早期發(fā)育中決定背腹軸形成、胚層建立、體節(jié)分化、組織或器官形成等一系列重要事件，并直接控制增殖、分化、極化、凋亡與抗凋亡等細胞命運;且與腫瘤發(fā)生密切相關。我們實驗室的研究工作圍繞Wnt信號轉導通路展開，在多個層面和系統(tǒng)中力求闡明Wnt信號通路的分子機制及相關的生物學功能。

　　在分子機制研究層面，將綜合應用生物化學與分子生物學、細胞生物學、發(fā)育生物學、結構生物學、及化學生物學等多種研究技術方法，研究目標蛋白質及相關復合物成員之間的相互作用關系、聚集狀態(tài)、修飾、定位、及蛋白質關鍵位點等等，以此為切入點，揭示Wnt信號轉導調控的新機制。同時，結合蛋白質組學等規(guī)?；慕M學手段，高通量篩選參與Wnt信號傳遞的新分子、新修飾及新位點，為機制研究提供更多線索。目前的工作主要包括Wnt信號膜質傳遞、細胞核內轉錄復合物調控、b-catenin入核機制等幾方面，我們的工作已經或將為這些環(huán)節(jié)的機制揭示取得突破性的進展。

　　基于Wnt信號重要的生物學功能，我們另一方面的工作是在模式生物系統(tǒng)中探索和驗證Wnt信號轉導通路的新功能。我們已經建立斑馬魚模式生物系統(tǒng)，除了常規(guī)的顯微注射mRNA或MO和原位雜交外，還新建了不同的基因突變或者轉基因品系，來鑒定我們研究的新分子、新機制在斑馬魚胚胎發(fā)育中所起到的作用;另一方面，我們已經建立了多個參與Wnt信號新分子的基因敲除小鼠，同時借助將這些基因敲除小鼠與axin2-RFP小鼠進行雜交繁育，建立一個熒光直觀檢測Wnt信號靶基因axin2表達水平的系統(tǒng)，不僅可以發(fā)現Wnt信號在小鼠胚胎發(fā)育時期發(fā)揮作用的新線索，也可以檢測研究目標基因是否在一些尚未發(fā)現的發(fā)育過程或環(huán)節(jié)具有新的功能。

　　Wnt信號通路的失調與腫瘤發(fā)生密切相關。我們開展了大規(guī)模基于Wnt信號活性調節(jié)的小分子化合物的篩選，尋找和鑒定顯著影響Wnt信號通路活性的小分子，并對其調控Wnt信號的靶點機制展開深入研究，使其成為Wnt信號機制與功能研究的工具藥，或者可能為腫瘤及其它疾病治療提供新的作用靶點和潛在的先導化合物。

承擔科研項目情況：

代表論著：

1. Jichang Han, Meng Yu, Yiqin Bai, Jianzhong Yu, Fei Jin, Chen Li, Rong Zeng, Jinghong Peng, Ao Li, Xiaomin Song, Hao Li*, Dianqing Wu*, Lin Li* (2020) Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors. Cancer Cell, 38: 1-13.
2. Wenhao Cui, Xiaoli He, Xiaohong Zhai, Huan Zhang, Yuanwei Zhang, Fei Jin, Xiaomin Song, Dianqing Wu, Qinghua Shi and Lin Li* (2020) CARF promotes spermatogonial self-renewal and proliferation through Wnt signaling pathway. Cell Disc., 6:85.
3. Yanan Li, Ying Cheng, Maoqi Zhang, Xiaoli He, Li Kong, Kexiang Zhou, Yunfu Zhou, Lin Li, Hongqi Tian*, Xiaomin Song*, and Yukun Cui*(2020) A New Compound with Increased Antitumor Activity by Cotargeting MEK and Pim-1. iScience, 23:101254.
4. Daisong Wang, Xin Hu, Chunye Liu, Yingying Jia, Yiqin Bai, Cheguo Cai, Jingqiang Wang, Lanyue Bai, Ruikai Yang, ChangDong Lin, Yi-Rong Liu, Shan Li, Feng Qiao, Ling Yao, Li Chen, Gaoxiang Ge, Hai Jiang, Dianfan Li, Lin Li, JianFeng Chen, Zhi-Ming Shao and Yi Arial Zeng* (2019) Protein C receptor is a therapeutic stem cell target in a distinct group of breast cancers. Cell Res., 29(10):832-845.
5. Qian Xiao, Jibo Wu, Wei-Jia Wang, Shiyang Chen , Yingxia Zheng , Xiaoqing Yu, Katrina Meeth, Mahnaz Sahraei, Alfred L. M. Bothwell, Lieping Chen, Marcus Bosenberg, Jianfeng Chen, Veronika Sexl, Le Sun, Lin Li*, Wenwen Tang*, and Dianqing Wu* (2018) DKK2 imparts tumor immunity evasion through b-catenin independent suppression of cytotoxic immune cell activation. Nature Med., 24(3): 262-270.
6. Dantong Li, Wenzhi Xue, Mei Li, Mei Dong, Jianwei Wang, Xianda Wang, Xiyue Li, Kai Chen, Wenjuan Zhang, Shuang Wu, Yingqi Zhang, Lei Gao, Yujie Chen, Jianfeng Chen, Bo O. Zhou, Yi Zhou, Xuebiao Yao, Lin Li, Dianqing Wu and Weijun Pan* (2018) VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche. Nature, 564:119-124.
7. Xiaoliang Zhu, Chunmao Yuan, Chenyang Tian, Chen Li, Fen Nie, Xiaomin Song, Rong Zeng, Dianqing Wu, Xiaojiang Hao*, and Lin Li* (2018) The plant sesquiterpene lactone parthenolide inhibits Wnt/b-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF. J. Biol. Chem., 1293(14):5335-5344.
8. Xiaoli He, Wenjuan Zhang, Chen Yan, Fen Nie, Chen Li, Xiaofen Liu, Cong Fei, Shengdi Li, Xiaomin Song, Yingying Jia, Rong Zeng, Dianqing Wu, Weijun Pan*, Xiaojiang Hao*, Lin Li* (2017) Chemical biology reveals CARF as a positive regulator of canonical Wnt signaling by promoting TCF/β-catenin transcriptional activity. Cell Disc., 3: 17003.
9. Shi Jiao, Chuanchuan Li, Qian Hao, Haofei Miao, Lei Zhang, Lin Li & Zhaocai Zhou* (2017) VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nat. Commun., 8:14058.
10. Li Mao, Chenglin Liu, Zhen Wang, Xiaofeng Niu, Liang Xue, Zhilei Zhou, Zhenying Cai, Meng Yu, Yixue Li*, Dianqing Wu*, Lin Li* (2016) A Genome-wide Loss-of-function Screening Method for Minimizing False-negatives caused by Functional Redundancy. Cell Res., 26:1067-1070.
11. Xin Wang, Yingying Jia, Cong Fei, Xiaomin Song*, and Lin Li*（2016） Activation/Proliferation-associated Protein 2 (Caprin-2) Positively Regulates CDK14/Cyclin Y-mediated Lipoprotein Receptor-related Protein 5 and 6 (LRP5/6) Constitutive Phosphorylation. J. Biol. Chem., 291(51): 26427-26434.
12. Xiangdong Lv, Zhijun Han, Hao Chen, Bo Yang, Xiaofeng Yang, Yuanxin Xia, Chenyu Pan, Lin Fu, Shuo Zhang, Hui Han, Min Wu, Zhaocai Zhou, Lei Zhang, Lin Li, Gang Wei*, Yun Zhao* (2016) A Positive Role for Polycomb in Transcriptional Regulation via H4K20me1. Cell Res., 26: 529-542.
13. 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 & Lei Zhang* (2015) Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis. Nature Commun., 6:6607.
14. Jian Hu, Qianying Yuan, Xue Kang, Yuanbo Qin, Lin Li, Ya Ha & Dianqing Wu* (2015) Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and disheveled. Nature Commun., 6:8205.
15. Ho-Jin Lee, Ju Bao, Ami Miller, Chi Zhang, Jibo Wu, Yiressy C. Baday, Cristina Guibao, Lin Li, Dianqing Wu, and Jie Zheng* (2015) Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled. J. Biol. Chem., 290(51): 30596-30606.
16. 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.
17. 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.
18. 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
19. 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
20. 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
21. 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
22. 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*, andLin Li* (2013) Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction. Nature Chem. Biol., 9, 579-585.
23. 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.
24. 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.
25. Wei Wei, Meng Li, Jiyong Wang, Fen Nie andLin Li* (2012) The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein. Mol. Cell Biol., 32, 3903-3912.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.

獲獎及榮譽：

研究組成員：

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