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Fu, Zheng

Zheng Fu

Primary Appointment


Contact Information

1340 JPA, Pinn Hall 5217
Charlottesville , VA 22908-0708
Telephone: 434-982-3204

Research Interests

Cell signaling of protein kinases in development and disease

Research Description

My broad research interest is the molecular and cellular basis of human disease, with a focus on aberrant signal transduction of protein kinases and phosphorylation. Protein kinases comprise one of the largest and most abundant gene families in humans. Both inherited germ-line and somatic mutations in kinase genes have been associated with many human diseases. Research in my lab is currently focused on the signaling mechanism and pathophysiologic functions of intestinal cell kinase (ICK), a ubiquitously expressed and highly conserved serine/threonine protein kinase. We are using both in vitro cell model systems and in vivo transgenic mouse models and a wide spectrum of experimental approaches in the areas of biochemistry, cell and developmental biology, and cancer biology to address the role of ICK in development, tissue injury repair and regeneration, and colon cancer/drug resistance. Project 1: Elucidate the molecular basis of the respiratory distress in human ECO Syndrome ICK is an essential gene in development. A loss-of-function mutation R272Q in human ICK gene is the causative mutation for human ECO (endocrine-cerebral-osteodysplasia) syndrome associated with developmental anomalies in multiple organ systems. A major research focus in my lab is to elucidate the cellular and molecular basis underlying the developmental defects that lead to the perinatal lethality phenotype of ECO using the Ick R272Q knock-in mouse model. Project 2: Elucidate the role of ICK in intestinal epithelial injury repair and regeneration ICK localizes specifically in the intestinal crypt where intestinal stem and progenitor cells reside. In vitro, we have demonstrated that ICK is important for intestinal epithelial cell proliferation and survival. Given that ICK expression is strongly induced in regenerating crypts following radiation injury, in collaboration with Dr. Steven Cohn?s lab at the UVA Digestive Health Research Center we are using an intestine-specific Ick knockout mouse model to examine the role of ICK in intestinal epithelial injury repair and regeneration. In collaboration with Dr. Richard Guerrant?s lab at the UVA Center for Global Health, we are also investigating the role of ICK in the maintenance of intestinal epithelial integrity in response to malnutrition and infection. Project 3: Investigate a novel ICK-GSK3 signaling mechanism in Colon Cancer and Drug Resistance A major challenge in current cancer therapy is the development of drug-resistance over time as a result of unexpected complexities in biological responses to drug treatment, such as compensatory and feed-back regulatory effects. Combinatory inhibition of multiple signaling pathways has emerged as an effective therapeutic strategy for the long-term cancer treatment. Developing novel targets toward key signaling molecules that inter-connect between synergistic or compensatory signaling cascades thus becomes essential for the combination therapy. Another major focus in the lab is to understand the biological significance of ICK over-expression in human colon cancer specimens and the oncogenic role of a newly-identified ICK-GSK3 signaling axis in CRC and rapamycin-resistance.

Selected Publications

Wang EJ, Gailey CD, Brautigan DL, Fu Z, Functional Alterations in Ciliogenesis-Associated Kinase 1 (CILK1) that Result from Mutations Linked to Juvenile Myoclonic Epilepsy., 2020; Cells. 9(3) PMID: 32178256 |

Oh YS, Wang EJ, Gailey CD, Brautigan DL, Allen BL, Fu Z, Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis., 2019; Cells. 8(7) PMID: 31277411 | PMCID: PMC6678984

Fu Z, Gailey CD, Wang EJ, Brautigan DL, Ciliogenesis associated kinase 1 (CILK1): targets and functions in various organ systems., 2019; FEBS letters. () PMID: 31506943 |

Tong Y, Park S, Wu D, Harris TE, Moskaluk CA, Brautigan DL, Fu Z, Modulation of GSK3? autoinhibition by Thr-7 and Thr-8., 2018; FEBS letters. () PMID: 29377106 |

Tong Y, Park SH, Wu D, Xu W, Guillot SJ, Jin L, Li X, Wang Y, Lin CS, Fu Z, An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome., 2017; FEBS letters. () PMID: 28380258 | PMCID: PMC5466854

Ding M, Jin L, Xie L, Park SH, Tong Y, Wu D, Chhabra AB, Fu Z, Li X, A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development., 2017; Calcified tissue international. () PMID: 29098359 |

Liu J, Bolick DT, Kolling GL, Fu Z, Guerrant RL, Protein Malnutrition Impairs Intestinal Epithelial Cell Turnover, a Potential Mechanism of Increased Cryptosporidiosis in a Murine Model., 2016; Infection and immunity. 84(12) 3542-3549 PMID: 27736783 | PMCID: PMC5116730

Bolick DT, Chen T, Alves LA, Tong Y, Wu D, Joyner LT, Ori? RB, Guerrant RL, Fu Z, Intestinal cell kinase is a novel participant in intestinal cell signaling responses to protein malnutrition., 2014; PloS one. 9(9) e106902 PMID: 25184386 | PMCID: PMC4153720

Chen T, Wu D, Moskaluk CA, Fu Z, Distinct expression patterns of ICK/MAK/MOK protein kinases in the intestine implicate functional diversity., 2013; PloS one. 8(11) e79359 PMID: 24244486 | PMCID: PMC3820702

Wu D, Chapman JR, Wang L, Harris TE, Shabanowitz J, Hunt DF, Fu Z, Intestinal cell kinase (ICK) promotes activation of mTOR complex 1 (mTORC1) through phosphorylation of Raptor Thr-908., 2012; The Journal of biological chemistry. 287(15) 12510-9 PMID: 22356909 | PMCID: PMC3321000

Fu Z, Kim J, Vidrich A, Sturgill TW, Cohn SM, Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells., 2009; American journal of physiology. Gastrointestinal and liver physiology. 297(4) G632-40 PMID: 19696144 | PMCID: PMC2763805

Fu Z, Larson KA, Chitta RK, Parker SA, Turk BE, Lawrence MW, Kaldis P, Galaktionov K, Cohn SM, Shabanowitz J, Hunt DF, Sturgill TW, Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase., 2006; Molecular and cellular biology. 26(22) 8639-54 PMID: 16954377 | PMCID: PMC1636783

Fu Z, Schroeder MJ, Shabanowitz J, Kaldis P, Togawa K, Rustgi AK, Hunt DF, Sturgill TW, Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase., 2005; Molecular and cellular biology. 25(14) 6047-64 PMID: 15988018 | PMCID: PMC1168834

Fu Z, Aronoff-Spencer E, Backer JM, Gerfen GJ, The structure of the inter-SH2 domain of class IA phosphoinositide 3-kinase determined by site-directed spin labeling EPR and homology modeling., 2003; Proceedings of the National Academy of Sciences of the United States of America. 100(6) 3275-80 PMID: 12629217 | PMCID: PMC152282