Zheng "John" Fu, PhD
Graduate School: University of Florida
Primary Appointment: Associate Professor, Medicine, Gastroenterology and Hepatology
Mechanistic insights into the regulation of gastrointestinal epithelial proliferation and differentiation; Signaling mechanisms underlying the cause and progression of colon cancer.
Email Address: firstname.lastname@example.org
The overall research interest of my lab is to understand the cellular and molecular mechanisms that govern cell growth, proliferation and differentiation, and their relationship to cancer. The current focus is on elucidating the role and the molecular mechanism of a novel protein kinase signaling pathway in the regulation of cell proliferation and differentiation in the intestinal epithelium. Intestinal cell kinase (ICK), originally cloned from the intestine and expressed in the intestinal crypt epithelium, is a highly conserved and ubiquitously expressed serine/threonine protein kinase. Although ICK has similarities in the catalytic domain to both CDKs and MAPKs and is regulated by dual phosphorylation within a MAPK-like TDY motif, its biological functions and signaling mechanism are still elusive.
Project 1: Role and
signaling mechanism of ICK in the regulation of cell proliferation and
differentiation in the intestinal epithelium
Our vitro studies using human colon cancer and intestinal epithelial cell lines have implicated an important role for ICK in supporting cell proliferation and G1 cell cycle progression. Recently we generated mice carrying floxed ICK allele. These mice will be crossed with mice carrying the Villin-Cre to generate mice with conditional ICK knockout in the intestine. Using this mouse model, we will ask whether intestine-specific ablation of the ICK gene is able to cause any phenotypic change in cell proliferation, differentiation, migration and lineage allocation in the intestinal epithelium during normal development and homeostasis and during crypt epithelium regeneration.
We have identified several key components of the ICK signaling cascade including its upstream yin-yang regulators, PP5 (protein phosphatase 5) and CCRK (cell cycle related kinase), and potential downstream targets including Scythe/BAT3, Raptor/mTORC1, GSK3/Wnt. Scythe/BAT3 is important for proliferation and apoptosis and is a novel regulator of p53 acetylation and H3K4 histone dimethylation. Both mTORC1 and Wnt pathways are key regulators of a wide range of cellular processes including cell growth, proliferation, and differentiation. Our goal is to dissect out the interplay between ICK and these signaling pathways in molecular details.
Project 2: Role of the ICK
signaling pathway in GI cancer
Our preliminary data have suggested that the expression and activity of ICK are significantly up-regulated in primary and metastatic human colon cancer specimens as compared to their normal tissue controls. We will determine the oncogenic potential of ICK in vitro and using xenografts. We also plan to generate a compound mouse model in which ICK gene is deleted in the background of known colon cancer mutations. This colon cancer mouse model will allow us to address whether ablation of the ICK gene in the intestine reduces tumor formation and/or progression. We are also interested in developing small molecule inhibitors for ICK and its upstream activating kinase CCRK to pursue translational research in GI cancer.
Wu, D., Chapman, J., Wang LF., Harris, T.E., Shabanowitz, J., Hunt, D.F., Fu, Z. (2012) Intestinal cell kinase (ICK) promotes activation of the mTOR complex 1 (mTORC1) through phosphorylation of Raptor Thr-908. J Bio Chem. In press.
Fu, Z., Kim, J., Vidrich, A., Sturgill, T.W., Cohn, S.M*. (2009) Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 297:632-640.
Fu, Z., Larson, K.A., Chitta, R.K., Parker, S.A., Turk, B.E., Lawrence, M.W., Kaldis, P., Galaktionov, K., Cohn, S.M., Shabanowitz, J., Hunt, D.F., Sturgill, T.W. (2006) Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase. Mol. Cell. Biol. 26(22):8639-8654.
Fu, Z., Schroeder, M.J., Shabanowitz, J., Kaldis, P., Tagawa, K., Rustgi, A.K., Hunt, D.F., Sturgill, T.W. (2005) Activation of a nuclear cdc2-related kinase within a mitogen-activated protein kinase- like TDY motif by autophosphorylation and cdk-activating kinase. Mol. Cell. Biol. 25(14):6047-6064.
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