教育经历
Education

2011年         新加坡南洋理工大学生物学博士
Ph. D., School of Biological Sciences, Nanyang Technological University, Singapore

2005年         新加坡国立大学生物医学学士
B.S., Biomedical Sciences, National University of Singapore, Singapore

工作经历
Professional Experience

2015年-             北京生命科学研究所研究员
Assistant Investigator, National Institute of Biological Sciences, Beijing, China

2010-2015年   美国约翰霍普金斯大学医学院，博士后
Postdoctoral Fellow, Johns Hopkins University School of Medicine, Maryland, USA

2006-2007年   新加坡南洋理工大学，项目主任
Project Officer, School of Biological Sciences, Nanyang Technological University, Singapore

2005-2006年   新加坡国立大学，科研助理
Research Assistant, Department of Biological Sciences, National University of Singapore, Singapore

研究概述
Research Description

我们实验室致力于研究新兴信号小分子的功能和机制。起调控作用的小分子，如G蛋白通路的二级信使三磷酸肌醇(IP3)和环核苷酸，被广泛研究。IP3被一系列的肌醇激酶进一步磷酸化生成多种多磷酸肌醇(IP4-8),其功能了解不多。其中，含有高能量，不稳定却广泛存在的焦磷酸肌醇(IP7/8)的作用原理尤为难解。我们之前发现IP7通过与激酶CK2互做而影响DNA损伤反应和细胞凋亡这些肿瘤发生相关的过程, 同时又注意到IP7在癌症转移过程中不可或缺。我们还报道了IP7 的合成酶IP6K1是介导紫外光激活Cullin 4 E3泛素连接酶的开关，但是相关生理意义和IP7的作用机制不清楚。通过研究焦磷酸肌醇特异的合成和水解酶的催化及调控机制，我们着眼于在细胞和小鼠模型里发掘焦磷酸肌醇介导的生理过程(如细胞迁移和肿瘤转移)，并揭示相关的信号通路。在此基础上，我们通过化学生物学和生物化学的方法寻找小分子的直接作用位点和作用模式，希望能够归纳出焦磷酸肌醇作用的普遍规律。基于焦磷酸肌醇在癌症等疾病发生过程中的作用，我们的机制和功能研究或可为治疗相关疾病提供新靶点。

The main interest of our group is to elucidate the function and mechanism of small molecules that are emerging messengers. Endogenous small molecules such as cyclic nucleotides and inositol triphosphates (IP3) are well-established 2nd messengers transducing extracellular stimulus into intracellular activities. IP3 is step-wise phosphorylated by a family of inositol phosphate kinases generating higher inositol polyphosphates (IP4-8) whose physiology remains poorly understood. In particular, inositol pyrophosphates (IP7/8) containing energetic pyrophosphate bond(s) are enigmatic inositol derivatives dynamically generated from inositol hexakisphosphate (IP6) by IP6 kinases (IP6Ks) and IP7 kinases (PPIP5Ks). We recently found that IP7 allosterically modulates CK2 to influence DNA damage response and cell death, processes linked to tumor initiation. Meanwhile, IP7 is essential for tumor metastasis. We also demonstrated that IP6K1 is a key switch dictating ultra-violet light-dependent activation of Cullin 4-based E3 ubiquitin ligases, the physiological relevance of which and mechanisms of action of IP7 remain unclear.  By studying the regulation of IP6Ks and enzymes leading to IP6 production in cell- and animal-based models, we aim to uncover the (patho)physiology (e.g. cell migration and cancer metastasis) and signal transduction pathways mediated by inositol pyrophosphates. On top of this, we employ chemical and biochemical approaches to identify effector modules and their mode of interactions, with the goal to unravel underlying principles of inositol pyrophosphate signaling. Given the key roles of IP6K/IP7 in tumor progression and other diseases processes, the mechanistic and functional insights gained from this investigation will hopefully provide new therapeutic targets.

发表文章

Publications

1. Scherer, PC., Ding, Y., Liu, Z., Xu, J., Haibin, Moa., Barrow, JC., Ning, W., Zheng, N., Snyder, SH., Rao F. Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc. Natl. Acad. Sci. 2016 Early Edition (doi: 10.1073/pnas.1525580113).

2. Rao F. #, Xu, J. #, Fu, C., Cha, J., Xu, R., Gadalla, MM., Wu, M., Fiedler, D., Barrow, JC., Snyder, SH. Inositol pyrophosphates promote cancer growth and metastasis by antagonizing the tumor suppressor LKB1. Proc. Natl. Acad. Sci. 2015 112, 1773-8 (#= Co-first author).
3. Rao F. #, Xu, J. #, Kahn, AB., Cha, J., Xu, R. Tyagi, R., Dang, Y., Chakraborty, A., Snyder, SH. Inositol hexakisphosphate kinase-1 mediates assembly/ disassembly of the CRL4-Signalosome complex to regulate DNA repair and cell death. Proc. Natl. Acad. Sci. 2014 111, 16005-16010. (#= Co-first author).
4. Rao F., Cha, J., Xu, J., Xu, R., Vandiver, MS., Tokhunt, RT., Wu, M., Fiedler, D., Barrow, J., Snyder, SH. Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. Mol. Cell 2014 54, 119-32.
5. Rao, F., See, RY., Zhang, D., Toh, DC., Liang Z-X. YybT is a signaling protein that contains a cyclic-di-nucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J. Biol. Chem. 2010, 285:473-82.
6. Tan E#., Rao F#., Pasunooti S., Pham TH., Soehano I., Turner MS., Liew CW., Lescar J., Pervushin K., Liang Z-X.  Solution structure of the PAS domain of a thermophilic YybT homolog reveals a potential ligand-binding site. J. Biol. Chem. 2013, 288:11949-59. (#= Co-first author).
7. Rao, F.*, Qi, Y., Murugan, E., Pasunooti, S., Ji, Q. 2’,3’-cAMP hydrolysis by metal-dependent phosphodiesterases containing DHH, EAL, and HD domains is non-specific: implications for PDE screening. Biochem. Biophys. Res. Commun. 2010, 398:500-505. (*= Corresponding author)
8. Rao, F., Pasunooti, S., Ng, Y., Zhuo, W., Lim, L., Liu, AW., Liang Z-X. Enzymatic synthesis of c-di-GMP using a thermophilic diguanylate cyclase. Anal. Biochem. 2009, 389:138-42.
9. Rao, F., Ji, Q., Soehano, I., Liang, Z-X. Unusual Heme-Binding PAS Domain from YybT Family Proteins. J. Bacteriol. 2011, 193:1543-1551.
10. Rao, F., Qi, Y., Chong, HS., Kotaka, M., Li, B., Lescar, J., Tang, K., Liang, Z-X. The functional role of a conserved loop in EAL domain-based c-di-GMP specific phosphodiesterase. J. Bacteriol. 2009, 191:4722-31
11. Rao, F., Yang, Y., Qi, Y., Liang, Z-X. Catalytic mechanism of C-di-GMP specific phosphodiesterase: a study of the EAL domain containing protein RocR from Psudomonas aeruginosa. J. Bacteriol. 2008, 190:3622-31
12. Rao, F., et al. Hong, Y. Medaka tert produces multiple variants with differential expression during differentiation in vitro and in vivo. Int. J. Biol .Sci. 2011, 7(4):426-439.

Patent
Liang, Z-X., Rao, F. Diguanylate cyclase method of producing the same and its use in the manufacture of cyclic-di-GMP and analogues thereof. 2014, US Patent No:  8,859,237.