Qingyun (Jim) Liu, Ph.D.,
Professor, Texas Therapeutics InstituteQingyun.Liu@uth.tmc.edu
The laboratory of Dr. Qingyun (Jim) Liu studies the roles of G protein-coupled receptors (GPCRs) in the initiation, growth, and metastasis of cancer for the discovery and development of noval anti-cancer treatments. The subfamily of leucine-rich repeat containing GPCRs, LGR4-6, are either over-expressed or mutated in multiple types of cancer with LGR5 specifically expressed in intestinal stem cells and colon cancer initiating cells. Our research is focused on the identification of endogenous ligands for these receptors, characterization of their roles in normal and cancer cell growth and migration, examination of their mechanisms of signal transduction, and discovery of potential therapeutics targeted at these receptors or their pathways.
In 1993, Dr. Liu joined Myriad Genetics as a Sr. Scientist and played a major role in the identification of the first breast cancer gene (BRCA1) and screening of BRCA1 mutations in breast and ovarian tumors. In 1995, Dr. Liu joined the Department of Human Genetics, Merck Research Laboratories as a Research Fellow and led efforts in the cloning and ligand identification of novel GPCRs as potential drug targets. His group successfully discovered a large number of GPCRs and their ligands, including the original cloning of HG38 (also named LGR5 and later shown to mark intestinal and hair follicle stem cells, and colon cancer stem cells by others), and demonstrated that the neuropeptide neuromedin U has important roles in the control of food intake in the brain. In 2002, Dr. Liu joined Lexicon Genetics, Inc. as Director of Molecular Pharmacology and later became Vice President of Pharmaceutical Discovery. He was responsible for the design and implementation of all in vitro assays, high-throughput screening, and medicinal chemistry support of all small molecular drug discovery effects at Lexicon. He also championed the discovery of two clinical development candidates targeted at the tryptophan hydroxylase type I (TPH1) that have entered Phase IIa clinical trials.
In 2009, Dr. Liu joined the Brown Foundation Institute of Molecular Medicine as a Professor and a member of the Texas Therapeutics Institute (TTI), a joint program of The University of Texas Health Science Center at Houston, The University of Texas M. D. Anderson Cancer Center and the Departments of Chemistry and Biochemistry at The University of Texas at Austin. He and other members of TTI will collaborate to help biomedical researchers transform their discoveries into novel diagnostics and treatments.
Research interests G protein-coupled receptors, the largest family of membrane-bound receptors, play critical roles in signal transduction, cell growth, differentiation, migration, and communication. They represent the single most successful class of drug targets, accounting for 30-50% of all drug sales. The receptors LGR4-6 are most homologous to members of the glycoprotein hormone receptor subfamily which have the characteristic long extracellular domain with 9-17 leucine-rich repeats and secreted proteins as ligands. LGR4-6 play important roles in growth and development, since knockout of LGR4 in the mouse causes reduced intrauterine growth and decreased viability, and knockout of LGR5 leads to neonatal lethality. All three genes are also involved in tumor initiation, growth and metastasis, as LGR4 and LGR5 are over-expressed in multiple types of tumor, and LGR6 is mutated in approximately 10% of colorectal cancer. Unfortunately, no ligands are known for these receptors, severely hampering the understanding of the roles of these receptors at the cellular and molecular level and making it nearly impossible to initiate drug discovery efforts targeted at these receptors. Our research interest is in finding the natural ligands of these receptors, examining their roles and mechanisms in growth and differentiation of both normal and malignant cells, and identifying drug-like molecules that are targeted at these receptors for the development of potential treatments for cancer and other diseases.
- Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y and et al. (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120-122.
- Liu Q, Neuhausen S, McClure M, Frye C, Weaver-Feldhaus J, Gruis NA, Eddington K, Allalunis-Turner MJ, Skolnick MH, Fujimura FK and et al. (1995) CDKN2 (MTS1) tumor suppressor gene mutations in human tumor cell lines. Oncogene 10:1061-1067.
- Liu Q, Yan YX, McClure M, Nakagawa H, Fujimura F and Rustgi AK (1995) MTS-1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines. Oncogene 10:619-622.
- McDonald T, Wang R, Bailey W, Xie G, Chen F, Caskey CT and Liu Q (1998) Identification and cloning of an orphan G protein-coupled receptor of the glycoprotein hormone receptor subfamily. Biochem Biophys Res Commun 247:266-270.
- Lynch KR, O'Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DL, Jr., Ford-Hutchinson AW, Caskey CT and Evans JF (1999) Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399:789-793.
- Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM, Zeng Z, Williams DL, Jr., Feighner SD, Nunes CN, Murphy B, Stair JN, Yu H, Jiang Q, Clements MK, Tan CP, McKee KK, Hreniuk DL, McDonald TP, Lynch KR, Evans JF, Austin CP, Caskey CT, Van der Ploeg LH and Liu Q (2000) Identification of receptors for neuromedin U and its role in feeding. Nature 406:70-74.
- Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, Feighner SD, Tan CP, Fukami T, Iwaasa H, Hreniuk DL, Morin NR, Sadowski SJ, Ito M, Ito M, Bansal A, Ky B, Figueroa DJ, Jiang Q, Austin CP, MacNeil DJ, Ishihara A, Ihara M, Kanatani A, Van der Ploeg LH, Howard AD and Liu Q (2001) Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci U S A 98:7564-7569.
- Shi ZC, Devasagayaraj A, Gu K, Jin H, Marinelli B, Samala L, Scott S, Stouch T, Tunoori A, Wang Y, Zang Y, Zhang C, Kimball SD, Main AJ, Sun W, Yang Q, Nouraldeen A, Yu XQ, Buxton E, Patel S, Nguyen N, Swaffield J, Powell DR, Wilson A and Liu Q (2008) Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders. J Med Chem 51:3684-3687.
- Liu Q, Yang Q, Sun W, Vogel P, Heydorn W, Yu XQ, Hu Z, Yu W, Jonas B, Pineda R, Calderon-Gay V, Germann M, O'Neill E, Brommage R, Cullinan E, Platt K, Wilson A, Powell D, Sands A, Zambrowicz B and Shi ZC (2008) Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J Pharmacol Exp Ther 325:47-55.
- Hu LA, Zhou T, Hamman BD and Liu Q (2008) A homogeneous G protein-coupled receptor ligand binding assay based on time-resolved fluorescence resonance energy transfer. Assay Drug Dev Technol 6:543-550.
- Hu LA, Tang P, Eslahi E, Zhou T, Barbosa J and Liu Q (2009) Identification of Surrogate Agonists and Antagonists for Orphan G Protein-coupled Receptor GPR139. J.Biomol Screen. 14:789-797.