Biography

Education

BS, Chemistry, Yantai University
MS, Chemistry, Xiamen University
PhD, Chemistry, University of Utah
Postdoctoral Training, Johns Hopkins University School of Medicine

Research Interests

• Illuminating the molecular mechanisms of aberrant activation of oncogenic kinases
• Dissecting the affected signaling pathways where oncogenic kinases lie in
• Examining the effects of posttranslational modification on enzyme activity and its physiological role
• Developing novel allosteric inhibitors disrupting protein-protein interactions in cancer cells

Protein phosphorylation, catalyzed by kinases, is the most universal mechanism of regulating protein function and transmitting signals throughout the cell. Aberrant activation of kinases causes dysfunction of cell signaling and regulatory pathways, resulting in numerous human diseases including cancer. Our laboratory is interested in the molecular logic of kinase function under normal and pathological conditions. The long-term goal of our research is to enhance our biochemical understanding of the origin of cancer and to provide a better molecular basis for cancer drug development.

We aim to elucidate the molecular mechanism of BRAF activation, regulation, and oncogenesis. BRAF kinase plays an important role in mitogen activated protein kinase (MAPK) signaling and harbors oncogenic mutations in about half of melanomas and in a smaller percentage in many other cancers. According to the currently accepted model, the first step in the BRAF activation process is recruitment of BRAF to the plasma membrane by receptor-activated RAS. The RAS/RAF interaction relieves autoinhibitory interactions to induce BRAF homo- and/or heterodimerization with other RAF kinases that enables allosteric activation of its cognate partner. Once activated, BRAF kinase phosphorylates and activates the dual-specificity kinase MEK1/2, which in turn phosphorylates and activates ERK1/2 to relay the signals throughout the cell. The outputs of the MAPK pathway are also regulated by negative feedback controls, among which ERK-mediated phosphorylation of RAF has been identified as one important negative feedback loop. By integrating techniques from biochemistry, chemistry, molecular biology, and cell biology, we study how a series of complex events, including membrane recruitment by RAS binding, phosphorylation/dephosphorylation, and protein-protein interactions, are coordinated to fine-tune the final output of the RAF signaling.

Selected Publications 

* denotes corresponding author

Nicholas Cope, Borna Novak, Zhiwei Liu, Maria Cavallo, Amber Gunderwala, Matthew Connolly, Zhihong Wang*. Analyses of the oncogenic BRAF variant reveal a kinase-independent function of BRAF D594G in activating MAPK signaling. J. Biol. Chem., 2020, 295, 2407-2420. (DOI: 10.1074/jbc.RA119.011536) (2020)

Nicolas Cope, Borna Novak, Christine Candelora, Kenneth Wong, Maria Cavallo, Amber Gunderwala, Zhiwei Liu, Yana Li, and Zhihong Wang*. Biochemical Characterization of Full-Length Oncogenic BRAF V600E Together with Molecular Dynamics Simulations Provide Insight into the Activation and Inhibition Mechanisms of RAF Kinases. ChemBioChem 2019, 20, 2850-2861. (DOI: 10.1002/cbic.20190266) (2019) 

* This article is selected as Very Important Paper and featured on the cover page.

Amber Gunderwala, Anushri Nimbvikar, Nicholas Cope, Zhijun Li, and Zhihong Wang*. Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF. ACS Chem.Bio. 2019, 14, 7, 1471-1480. (DOI: 10.1021/acschembio.9b00191) (2019)

Nicolas Cope, Christine Candelora, Kenneth Wong, Sujeet Kumar, Haihan Nan, Michael Grasso, Borna Novak, Yana Li, Ronen Marmorstein, and Zhihong Wang*. Mechanism of BRAF Activation Through Biochemical Characterization of the Recombinant Full-Length Protein. ChemBioChem 19(18), 1988-1997 (2018)

* This article is collected under ChemBioTalent Issue featuring young researchers in the field of chemical biology.

Zhihong Wang*, Min-Sik Kim, Isabel Martinez Ferrando, Anthony Koleske, Akhilesh Pandey, and Philip A. Cole*. Analysis of Cellular Tyrosine Phosphorylation via Chemical Rescue of Conditionally Active Abl Kinase. Biochemistry, 57 (8), 1390–1398 (2018)

Yang W. Zhang, Zhihong Wang, Wenbing Xie, Yi Cai, Limin Xia, Hariharan Easwaran, Ray-Whay Chiu Yen, and Stephen B. Baylin. Acetylation Enhances TET2 Function in Protecting Against Abnormal DNA Methylation During Oxidative Stress. Molecular Cell 65(2), 323-335 (2017). (PMCID: PMC5260804)

Zhihong Wang* and Christian Candelora. In Vitro Enzyme Kinetics Analysis of Full-Length EGFR Purified from HEK293 Cells. Methods in Molecular Biology. 1487, 23-33. (2016)

Jennifer M. Kavran, Jacqueline M. McCabe, Patrick O. Byrne, Mary Katherine Tarrant, Zhihong Wang, Alexander Ramek, Sarvenaz Sarabipour, Yibing Shan, David E. Shaw, Kalina Hristova, Philip A. Cole, and Daniel J. Leahy. How IGF-1 Activates Its Receptor. eLife 2014;3:e03772 (2014). (PMCID: PMC4381924)

Zhihong Wang and Philip A. Cole. Catalytic Mechanisms and Regulation of Protein Kinases. Methods in Enzymology. 548, 1-21. (2014). (PMCID: PMC4373616)

Zhihong Wang, Lily Raines, Richard M. Hooy, Heather Roberson, Daniel J. Leahy, and Philip A. Cole. Tyrosine Phosphorylation of Mig6 Reduces Its Inhibition of the Epidermal Growth Factor Receptor. ACS Chem. Biol. 203, 2372-2376 (2013). (PMCID: PMC3830645)

Zhihong Wang, Patti A. Longo, Mary Katherine Tarrant, Kwangsoo Kim, Sarah Head, Daniel J. Leahy, and Philip A. Cole. Mechanistic Insights into the Activation of Oncogenic Forms of EGF Receptor. Nat. Struct. Mol. Biol.18, 1388-1393 (2011). (PMCID: PMC3230693)

Kathryn E. Muratore, Markus A. Seeliger, Zhihong Wang, Dina Fomina, Johnathan Neiswinger, James J. Havranek, David Baker, John Kuriyan, and Philip A. Cole. Comparative Analysis of Mutant Tyrosine Kinase Chemical Rescue. Biochemistry 48, 3378-3386 (2009). (PMCID: PMC2714740)

Note: A full list of publications can be found at Pubmed