Department Affiliation: Pharmacology and Molecular Sciences
Degree: Ph.D., University of Chicago
Rank: Associate Professor
Telephone Number: 410-502-0173; Lab: 410-614-2892
Fax Number: 410-955-3023
E-mail address: jzhang32@bs.jhmi.edu
School of Medicine Address: 307 Hunterian Building, 725 N. Wolfe St., Baltimore, MD 21205
Spatiotemporal-Regulation of Signal Transduction
We are interested in the spatiotemporal regulation of cell signaling, with a particular focus on important signaling molecules such as protein kinases and second messengers.
Recent years have seen tremendous progress in identification of signaling components constituting a network of pathways that control cellular processes. Less well developed is our understanding of how these components are precisely regulated to achieve signaling specificity within a living cell, which may be reacting to multiple inputs simultaneously. The key is believed to lie in the spatiotemporal information encoded in a particular cellular context. We are investigating the molecular basis and cellular consequences of such spatiotemporal regulation by combining biochemical and biophysical approaches, including live-cell fluorescence microscopy.
To achieve a comprehensive understanding of the spatiotemporal regulation of signal transduction, tools that are capable of tracking signaling dynamics in living systems with single-cell resolution are essential. To generate such tools for a broad spectrum of signaling molecules, we have developed several general strategies for engineering fluorescent biosensors to track the activities of second messengers, kinases and phosphatases. We are currently applying these molecular tools, in combination with other cellular and molecular techniques, to investigate the spatiotemporal regulation or dysregulation of several signaling pathways, such as cAMP/PKA, PI3K/Akt and MAPK pathways, in the context of cell migration, energy metabolism and cancer development. Quantitative measurement from live-cell fluorescence imaging is combined with mechanistic computational modeling for systems analyses of signaling networks. Furthermore, in our efforts to “illuminate the kinome”, we are building our knowledge about this important family of signaling regulators by undertaking large-scale studies including proteome-wide identification of kinase substrates.
New technologies are also being developed in the lab, for example, for manipulating molecular forces and perturbing biochemical activities in living systems. The goal is to enable native biochemistry and biophysics studies to address many outstanding questions about the properties and behaviors of biomolecules in their native biological context.
The application of these novel technologies for studying signaling molecules in living systems should provide a better understanding of the molecular changes that regulate the cells’ inner workings, adding time and space dimensions and dynamic information to the current map of signal transduction networks. It is our hope that these studies will eventually lead to development of more effective therapeutic treatments that target the defects arising from dysregulated kinases and second messengers.
Representative Publications:
- Gao, X. and Zhang, J. Spatiotemporal Analysis of Differential Akt Regulation in Plasma Membrane Microdomains. Mol. Biol. Cell 19(10):4366-4373, 2008. Pub Med Reference
- Newman, R.H. and Zhang, J. Visualization of Phosphatase Activity in Living Cells with a FRET-based Calcineurin Activity Sensor. Mol. BioSys. 4(6):496-501, 2008. Pub Med Reference
- Violin, J.D.*, DiPilato, L.M.*, Elston, T.C.*, Yildrim, N.†, Zhang, J.†, and Lefkowitz, R.J.† ß2-Adrenergic Receptor Signaling and Desensitization Elucidated by Quantitative Modeling of Real-Time cAMP Dynamics. *Equal contribution. † Co-corresponding authors J. Biol. Chem. 2008; 283(5):2949-2961 Pub Med Reference
- Allen, M.D. and Zhang, J. A Tunable FRET Circuit for Engineering Fluorescent Biosensors. Angew. Chem. Int. Ed Engl. 47(3):500-502, 2008. Pub Med Reference
- Ananthanarayanan, B., Fosbrink, M., Rahdar, M. and Zhang, J. Live-Cell Molecular Analysis of Akt Activation Reveals Roles for Activation Loop Phosphorylation. J. Biol. Chem. 282(50):36634-36641, 2007. Pub Med Reference
- Zhang, J. and Allen, M.D. FRET-based Kinase Biosensors – Illuminating the Kinome. Mol. Biosyst. 3: 759-765, 3007. Pub Med Reference
- Allen, M.D. and Zhang, J. Subcellular dynamics of protein kinase A activity visualized by FRET-based reporters. Biochem. Biophys. Res. Commun. 348:716-721, 2006. Pub Med Reference
- Allen, M.D., DiPilato, L.M., Rahdar, M., Ren, Y.R., Chong, C., Liu, J.O. and Zhang J. Reading dynamic kinase activity in living cells for high-throughput screening. ACS Chem. Biol. 1:371-376, 2006. Pub Med Reference
- Ananthanarayanan, B., Ni, Q., and Zhang, J. Signal propagation from membrane messengers to nuclear effectors revealed by reporters of phosphoinositide dynamics and Akt activity. Proc. Natl. Acad. Sci. USA 102:15081-15086, 2005. Pub Med Reference
- DiPilato, L.M., Cheng, X., and Zhang, J. Fluorescent Indicators of cAMP and Epac Activation Reveal Differential Dynamics of cAMP Signaling within Discrete Subcellular Compartments. Proc. Natl. Acad. Sci. USA 101: 16513-16518, 2004. Pub Med Reference
For a complete list of publications, please click here.
Support from NIH Director’s Pioneer Award, NIH-NIDDK, 3M, and FAMRI.
Other graduate programs in which Dr. Zhang participates:
BCMB Graduate Program
Anti-Cancer Drug Development Program
Chemistry-Biology Interface Program (CBI)
Neuroscience Graduate Program
