Research Summary:

Structural Biology and Translational Cancer Research

1.  Structural Biology of the Mechanisms of Activation of G-proteins by GPCRs

The signaling from G-protein-coupled receptors (GPCRs) to G-proteins is one of the main signaling systems used in biology.  Although we have an outline of this signaling system, the molecular bases for many steps in this signaling cascade are poorly understood.  One of the pressing issues is how GPCRs activate G-proteins.  Currently we use the cryo-electron microscopy (Cryo-EM) technique to investigate this question.

2.  Tumor Metastasis, Cancer Immunotherapy and Drug Development

Tumor metastasis is the major cause of death of cancer patients, responsible for more than 90% of all cancer deaths.  We focus on tumor metastasis, more specifically, on tumor cell migration and invasion.  Our long-term goal of this research program is to reveal the critical proteins for tumor cell migration and invasion, and to use these proteins as targets for drug development to block tumor metastasis.  In addition, we are investigating the roles of dendritic cells and macrophages in cancer immunotherapy.

3.  G-protein Signaling in Blood Vessel Formation and Bone Homeostasis

Our long-term goal of this research program is to discover the signaling pathways regulated by G-proteins and the physiological functions of these modulations.  Currently we focus on the signaling mechanisms and functions by which G-protein G13 controls blood vessel formation, and bone homeostasis. We are investigating the roles of G13 in endothelial and osteoclast cell proliferation, remodeling and migration.

Recent Publications:

  1. Nakano, S, Inoue, K, Xu, C, Deng, Z, Syrovatkina, V, Vitone, G et al.. G-protein Gα13 functions as a cytoskeletal and mitochondrial regulator to restrain osteoclast function. Sci Rep. 2019;9 (1):4236. doi: 10.1038/s41598-019-40974-z. PubMed PMID:30862896 PubMed Central PMC6414604.
  2. McGuire, S, Kara, B, Hart, PC, Montag, A, Wroblewski, K, Fazal, S et al.. Inhibition of fascin in cancer and stromal cells blocks ovarian cancer metastasis. Gynecol. Oncol. 2019;153 (2):405-415. doi: 10.1016/j.ygyno.2019.01.020. PubMed PMID:30797592 PubMed Central PMC6486884.
  3. Syrovatkina, V, Huang, XY. Signaling mechanisms and physiological functions of G-protein Gα13 in blood vessel formation, bone homeostasis, and cancer. Protein Sci. 2019;28 (2):305-312. doi: 10.1002/pro.3531. PubMed PMID:30345641 PubMed Central PMC6319754.
  4. Huang, J, Dey, R, Wang, Y, Jakoncic, J, Kurinov, I, Huang, XY et al.. Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor. J. Mol. Biol. 2018;430 (9):1324-1335. doi: 10.1016/j.jmb.2018.03.009. PubMed PMID:29573988 PubMed Central PMC5916032.
  5. Wang, L, Wang, D, Xing, B, Tan, YC, Huang, J, Liu, B et al.. G-Protein Gα13 Functions with Abl Kinase to Regulate Actin Cytoskeletal Reorganization. J. Mol. Biol. 2017;429 (24):3836-3849. doi: 10.1016/j.jmb.2017.10.020. PubMed PMID:29079481 PubMed Central PMC5705571.
  6. Syrovatkina, V, Alegre, KO, Dey, R, Huang, XY. Regulation, Signaling, and Physiological Functions of G-Proteins. J. Mol. Biol. 2016;428 (19):3850-68. doi: 10.1016/j.jmb.2016.08.002. PubMed PMID:27515397 PubMed Central PMC5023507.
  7. Han, S, Huang, J, Liu, B, Xing, B, Bordeleau, F, Reinhart-King, CA et al.. Improving fascin inhibitors to block tumor cell migration and metastasis. Mol Oncol. 2016;10 (7):966-80. doi: 10.1016/j.molonc.2016.03.006. PubMed PMID:27071719 PubMed Central PMC5423182.
  8. Singhvi, A, Liu, B, Friedman, CJ, Fong, J, Lu, Y, Huang, XY et al.. A Glial K/Cl Transporter Controls Neuronal Receptive Ending Shape by Chloride Inhibition of an rGC. Cell. 2016;165 (4):936-48. doi: 10.1016/j.cell.2016.03.026. PubMed PMID:27062922 PubMed Central PMC4860081.
  9. Huang, J, Chen, S, Zhang, JJ, Huang, XY. Ligand occupancy in crystal structure of β1-adrenergic G protein-coupled receptor. Nat. Struct. Mol. Biol. 2015;22 (12):942. doi: 10.1038/nsmb.3131. PubMed PMID:26643843 .
  10. Zhang, W, Qu, X, Chen, B, Snyder, M, Wang, M, Li, B et al.. Critical Roles of STAT3 in β-Adrenergic Functions in the Heart. Circulation. 2016;133 (1):48-61. doi: 10.1161/CIRCULATIONAHA.115.017472. PubMed PMID:26628621 PubMed Central PMC4698100.
  11. Huang, FK, Han, S, Xing, B, Huang, J, Liu, B, Bordeleau, F et al.. Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization. Nat Commun. 2015;6 :7465. doi: 10.1038/ncomms8465. PubMed PMID:26081695 .
  12. Huang, J, Sun, Y, Zhang, JJ, Huang, XY. Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor. J. Biol. Chem. 2015;290 (1):272-83. doi: 10.1074/jbc.M114.608661. PubMed PMID:25414258 PubMed Central PMC4281731.
  13. Snyder, M, Huang, J, Huang, XY, Zhang, JJ. A signal transducer and activator of transcription 3·Nuclear Factor κB (Stat3·NFκB) complex is necessary for the expression of fascin in metastatic breast cancer cells in response to interleukin (IL)-6 and tumor necrosis factor (TNF)-α. J. Biol. Chem. 2014;289 (43):30082-9. doi: 10.1074/jbc.M114.591719. PubMed PMID:25213863 PubMed Central PMC4208015.
  14. Huang, J, Chen, S, Zhang, JJ, Huang, XY. Crystal structure of oligomeric β1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat. Struct. Mol. Biol. 2013;20 (4):419-25. doi: 10.1038/nsmb.2504. PubMed PMID:23435379 PubMed Central PMC3618578.
  15. Yang, S, Huang, FK, Huang, J, Chen, S, Jakoncic, J, Leo-Macias, A et al.. Molecular mechanism of fascin function in filopodial formation. J. Biol. Chem. 2013;288 (1):274-84. doi: 10.1074/jbc.M112.427971. PubMed PMID:23184945 PubMed Central PMC3537022.
  16. Yang, S, Zhang, JJ, Huang, XY. Mouse models for tumor metastasis. Methods Mol. Biol. 2012;928 :221-8. doi: 10.1007/978-1-62703-008-3_17. PubMed PMID:22956145 PubMed Central PMC3674868.
  17. Snyder, M, Huang, XY, Zhang, JJ. Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration. J. Biol. Chem. 2011;286 (45):38886-93. doi: 10.1074/jbc.M111.286245. PubMed PMID:21937440 PubMed Central PMC3234713.
  18. Snyder, M, Huang, XY, Zhang, JJ. Stat3 is essential for neuronal differentiation through direct transcriptional regulation of the Sox6 gene. FEBS Lett. 2011;585 (1):148-52. doi: 10.1016/j.febslet.2010.11.030. PubMed PMID:21094641 PubMed Central PMC3022371.
  19. Snyder, M, Huang, XY, Zhang, JJ. Stat3 directly controls the expression of Tbx5, Nkx2.5, and GATA4 and is essential for cardiomyocyte differentiation of P19CL6 cells. J. Biol. Chem. 2010;285 (31):23639-46. doi: 10.1074/jbc.M110.101063. PubMed PMID:20522556 PubMed Central PMC2911296.
  20. Chen, L, Yang, S, Jakoncic, J, Zhang, JJ, Huang, XY. Migrastatin analogues target fascin to block tumour metastasis. Nature. 2010;464 (7291):1062-6. doi: 10.1038/nature08978. PubMed PMID:20393565 PubMed Central PMC2857318.
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