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. Li, K, Zhang, Z, Wang, K, Huang, XY, Lin, ZJ. Development and validation of an LC-MS/MS method for the quantification of fascin proteins in human serum. Bioanalysis. 2022; :. doi: 10.4155/bio-2022-0121. PubMed PMID:36154676 .
  2. Su, M, Paknejad, N, Zhu, L, Wang, J, Do, HN, Miao, Y et al.. Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies. Nat Commun. 2022;13 (1):4095. doi: 10.1038/s41467-022-31823-1. PubMed PMID:35835792 PubMed Central PMC9283524.
  3. Zhao, LP, Hu, JH, Hu, D, Wang, HJ, Huang, CG, Luo, RH et al.. Hyperprogression, a challenge of PD-1/PD-L1 inhibitors treatments: potential mechanisms and coping strategies. Biomed Pharmacother. 2022;150 :112949. doi: 10.1016/j.biopha.2022.112949. PubMed PMID:35447545 .
  4. Liu, S, Paknejad, N, Zhu, L, Kihara, Y, Ray, M, Chun, J et al.. Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun. 2022;13 (1):731. doi: 10.1038/s41467-022-28417-2. PubMed PMID:35136060 PubMed Central PMC8826421.
  5. Alegre, KO, Paknejad, N, Su, M, Lou, JS, Huang, J, Jordan, KD et al.. Structural basis and mechanism of activation of two different families of G proteins by the same GPCR. Nat Struct Mol Biol. 2021;28 (11):936-944. doi: 10.1038/s41594-021-00679-2. PubMed PMID:34759376 PubMed Central PMC8719444.
  6. Zhao, Z, Wang, Y, Zhang, JJ, Huang, XY. Fascin Inhibitors Decrease Cell Migration and Adhesion While Increase Overall Survival of Mice Bearing Bladder Cancers. Cancers (Basel). 2021;13 (11):. doi: 10.3390/cancers13112698. PubMed PMID:34070777 PubMed Central PMC8199464.
  7. Wang, Y, Song, M, Liu, M, Zhang, G, Zhang, X, Li, MO et al.. Fascin inhibitor increases intratumoral dendritic cell activation and anti-cancer immunity. Cell Rep. 2021;35 (1):108948. doi: 10.1016/j.celrep.2021.108948. PubMed PMID:33826900 PubMed Central PMC8050791.
  8. Nader, N, Dib, M, Hodeify, R, Courjaret, R, Elmi, A, Hammad, AS et al.. Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2. PLoS Biol. 2020;18 (11):e3000901. doi: 10.1371/journal.pbio.3000901. PubMed PMID:33137110 PubMed Central PMC7660923.
  9. Wang, Y, Zhang, JJ, Huang, XY. Anti-Metastasis Fascin Inhibitors Decrease the Growth of Specific Subtypes of Cancers. Cancers (Basel). 2020;12 (8):. doi: 10.3390/cancers12082287. PubMed PMID:32824026 PubMed Central PMC7466159.
  10. Su, M, Zhu, L, Zhang, Y, Paknejad, N, Dey, R, Huang, J et al.. Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor. Mol Cell. 2020;80 (1):59-71.e4. doi: 10.1016/j.molcel.2020.08.001. PubMed PMID:32818430 PubMed Central PMC7541785.
  11. Au, CC, Furness, JB, Britt, K, Oshchepkova, S, Ladumor, H, Soo, KY et al.. Three-dimensional growth of breast cancer cells potentiates the anti-tumor effects of unacylated ghrelin and AZP-531. Elife. 2020;9 :. doi: 10.7554/eLife.56913. PubMed PMID:32667883 PubMed Central PMC7363447.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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 .
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