Associate Prof. Rao obtained his B.Sc. (2001-2005) and Ph.D. (2007-2011) from National University of Singapore and Nanyang Technological University, respectively. His postdoctoral training was conducted at Johns Hopkins University School of Medicine from 2010-2015. After an assistant investigator appointment at the National Institute of Biological Sciences, Beijing, he joined SUSTech as an associate professor in July 2016.
1. Signaling Principles of the Inositol Pyrophosphate IP7
The main interest of our group is to elucidate the function and mechanism of small molecules that are emerging messengers. The GPCR IP3 is step-wise phosphorylated 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 (IP7Ks). We have previously uncovered IP7 as a critical determinant of cancer cell fate (apoptosis vs metastasis). 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 pyrophosphate metabolites, especially in the context of disease microenviroments. 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 metabolic diseases, the mechanistic and functional insights gained from this investigation will hopefully provide new therapeutic targets.
2. Cullin Ring E3 ligases(CRLs) are a major family of protein ubiquitination
Machineries that are aberrantly active in cancer and mediate the degradation of many proteins involved in carcinogenic process such as cell survival, growth, metabolism, autophagy, migration and immune evasion. Neddylation activates CRL. The COP9 signalosome (CSN) binds, deneddylates, and inactivates CRL. Our group recently discovered a role for the inositol polyphosphate metabolites in assembling and disassembling CRL-CSN complexes. How such metabolite-dependent CRL regulation integrates into cellular physiology, especially in context of nutrient sensing, is the emphasis.
2016 – Present Associate Professor, Department of Biology, SUSTech
2015-2016 Assistant Investigator, National Institute of Biological Sciences, Beijing, China
2011-2015 Postdoctoral Fellow, Johns Hopkins University School of Medicine, Maryland, USA
2006-2007 Project Officer, School of Biological Sciences, Nanyang Technological University, Singapore
2005-2006 Research Assistant, Department of Biological Sciences, National University of Singapore, Singapore
2007-2011 Ph. D., School of Biological Sciences, Nanyang Technological University, Singapore
2001-2005 B.Sc., Biomedical Sciences, National University of Singapore, Singapore
◆ We are currently recruiting motivated lab members including students and employee at all levels.
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1.Lin H. #, Zhang XZ. #, Liu L., Fu QY., Zang CL., Ding Y., Xu ZX., He SN., Yang XL., Wei XY., Mao HB., Cui YS, Wei Yi., Zhou CZ., Du LL., Huang N., Zheng N., Wang T., and Rao F.*. Molecular basis of metabolite-dependent Cullin RING ligase deneddylation by the COP9 Siganalosome. Proc Natl Acad Sci USA. 2020, DOI: 10.1073/pnas.1911998117.
2.Rao F.*, Lin H., Su Y.. Cullin RING ligase regulation by the COP9 Signalosome: Structural Mechanisms and New Physiologic Players. Adv. Exp. Med. Biol. 2020, 1217, 47-60. (Invited Chapter of the book “Cullin RING Ligases and Neddylation”)
3.Zhang XZ., Rao F.*. Are inositol polyphosphates the missing link in dynamic Cullin RING ligase regulation by the COP9 Signalosome? Biomolecules. Special Issue on “ZOMES”: 2019, 9, 349.
4.魏文毅*、孙毅*、曹诚、常智杰、陈策实、陈佺、程金科、冯仁田、高大明、胡荣贵、贾立军、姜天霞、金建平、李汇华、李卫、刘翠华、饶枫、商瑜、宋质银、万勇、王平、王占新、吴缅、吴乔、谢旗、谢松波、谢志平、徐平、许执恒、杨波、阳成伟、应美丹、张宏冰、张令强、赵永超、周军、朱军、王琳芳、张宏、王琛、邱小波*. 类泛素蛋白及其中文命名（Ubiquitin-like Proteins and their Chinese Nomenclatures）. 科学通报. 2018, 63(25):2564-2569.
5.Fu C., Tyagi R., Chin AC., Rojas T., Li RJ., Guha P., Bernstein IA., Rao F., Xu R., Cha JY., Xu J., Snowman AM., Semenza GL., Snyder SH.*. Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α [J]. Circulation Research. 2018 Feb 2, 122(3):457-472.
6.Scherer PC., Zaccor NW., Neumann NM., Vasavda C., Barrow R., Ewald AJ., Rao F., Sumner CJ., Snyder SH.*. TRPV1 is a physiological regulator of μ-opioid receptors[J]. Proc Natl Acad Sci USA. 2017 Dec 19, 114(51):13561-13566.
7.Scherer PC.#, Ding Y.#, Liu Z., Xu J., Mao H., Barrow JC., Wei N., Zheng N., Snyder SH*, Rao F.*. Inositol hexakisphosphate（IP6） generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc Natl Acad Sci USA. 2016, 113, 3503-8.
8.Rao F.#, Xu J.#, Fu C., Cha JY., 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 USA. 2015 112, 1773-8.
9.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 USA. 2014, 111, 16005-16010.
10.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.
11.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.
12.Xu R., Sen N., Paul BD., Rao F., Vandiver MS., Snyder SH.*. Inositol phosphate multikinase catalyzes the acetylation of p53 by p300, thereby functioning as a p53 transcriptional co-activator. Science Signaling. 2013, 6, ra22: 1-10.
13.Vandiver MS., Paul BD., Xu R., Karuppagounder S., Rao F., Snowman AM., Ko HS., Li YI., Sen N., Dawson VL., Dawson TM., Snyder SH.*. Sulfhydration mediates neuroprotective actions of Parkin. Nat Commun. 2013, 4:1626.
14.Xu R, Paul BD, Smith DR, Tyagi R, Rao F., Khan AB., Blech DJ., Vandiver MS., Harraz MM., Guha P., Ahmed I., Sen N., Gallagher M., Snyder SH.*. Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction. Proc Natl Acad Sci USA. 2013, 6, 110, 16181-.
15.Cha J., Xu J., Paul BD., Rao F., Ho G., Snyder SH.*. Dexras1 Mediates adipogenesis and diet-induced obesity. Proc Natl Acad Sci USA. 2013, 110, 20575-.
16.Chia WS., Chia, XD., Rao F., Bar-Nun S., Geifman S.*. ATP binding to p97/VCP regulates selective recruitment of adaptors to its proximal N-domain. PLOS ONE. 2012, 7: e50490.
17.Chen M.W., Kotaka M., Vonrhein C., Bricogne G., Rao F., Chuah M.L., Svergun D., Schneider G., Liang Z-X.*. and Lescar J. *. Structural insights into the regulatory mechanism of the response regulator RocR from Pseudomonas aeruginosa in cyclic di-GMP signaling. J Bacteriol. 2012, 194:4837-4846.
18.Rao, F., Wang T., Li M., Li Z., Hong N., Zhao H., Yan Y., Lu W., Chen T., Wang W., Lim M., Yuan Y., Liu L., Zeng L., Wei Q., Guan G., Li C., Hong Y.*. Medaka tertproduces multiple variants with differential expression during differentiation in vitro and in vivo. Biol. Sci. 2011, 7(4):426-439.
19.Rao, F., Ji, Q., Soehano I., Liang Z-X.*. Unusual Heme-Binding PAS Domain from YybT Family Proteins. J Bacteriol. 2011, 193:1543-1551.
20.Murugan E., Kong R., Sun H., Rao F., Liang, Z-X. Expression, purification and characterization of acyl carrier protein phosphodiesterase from Pseudomonas aeruginosa. Protein Expres. Purif. 2010, 71:132-138.
21.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.
22.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. Res. Commun.2010, 398:500-505.
23.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.
24.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.
25.Qi Y., Rao F., Luo Z., Liang Z- X.*. A flavin cofactor-binding PAS domain regulates C-di-GMP synthesis in AxDGC2 from Acetobacter xylinum. Biochemistry. 2009, 48:10275-85.
26.Kotaka M.*., Dutta S., Lee H.C., Lim M., Wong Y., Rao F., Mitchell E.P., Liang Z-X, Lescar JX.*. Expression, purification and preliminary crystallographic analysis of Pseudomonas aeruginosaRocR protein. Acta Crystallogr. F. 2009, 65: 1035-1038.
27.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.
(*= Corresponding Author ; #=Co-first Author )
1. 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.