Department of Pharmacology and Molecular Sciences
B.S. 1995, Tsinghua University
Ph.D. 2000, University of Chicago
307 Hunterian Building
725 N. Wolfe Street
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 of several signaling pathways, such as cAMP/PKA,Ca2+/calcineurin, PI3K/Akt, MAPK and AMPK pathways, in the context of energy metabolism, cell differentiation or insulin secretion by β cells. 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 activity 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.
Support from NIH Director's Pioneer Award and NIH-NIDDK.
Dedecker, P.†, G.C.H. Mo, T. Dertinger, and J. Zhang†. (2012) Widely accessible method for superresolution fluorescence imaging of living systems. †Co-corresponding authors. Proc. Natl. Acad. Sci. USA 109:10909-10914.
Sample, V.*, L.M. DiPlato*, J. Wang, Q. Ni, J.J. Saucerman†, and J. Zhang†. (2012) Regulation of nuclear PKA revealed by spatiotemporal manipulation of cAMP. *Equal contribution. †Co-corresponding authors. Nature Chem. Biol. 8:375-382.
Gao, X., P. Lowry, X. Zhou, C. Depry, Z. Wei, G.W. Wong, and J. Zhang. (2011) P13K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains. Proc. Natl. Acad. Sci. USA 108:14509-14514.
Herbst, K.J., M.D. Allen, and J. Zhang. (2011) Spatiotemporally regulated PKA activity is a critical regulator of growth factor-stimulated ERK signaling in PC12 cells. Mol. Cell Biol. (in press)
Herbst, K.J., M.D. Allen, and J. Zhang. (2011) Luminescent kinase activity biosensors based on a versatile molecular switch. J. Am. Chem. Soc. 133:5676-5679.
Ni, Q.*, A. Ganesan*, N. Aye-Han*, X. Gao, M.D. Allen, A. Levchenko†, and J. Zhang†. (2011) Signaling diversity of PKA via a Ca2+-cAMP-PKA oscillatory circuit. *Equal contribution. †Co-corresponding authors. Nature Chem. Biol. 7:34-40.
Herbst, K.J., C. Coltharp, L.M. Amzel, and Zhang J. (2011) Direct activation of Epac by sulfonylurea is isoform selective. Chem. Biol. 18:243-251.
Newman, R.H., M. Fosbrink, and J. Zhang. (2011) Genetically encoded fluorescent biosensors for tracking signaling dynamics in living cells. Chem. Rev. 111:3614-66.
Mehta, S., and J. Zhang. (2011) Reporting from the field ? Genetically-encoded fluorescent reporters uncover signaling dynamics in living biological systems. Annu. Rev. Biochem. 80:375-401.
Fosbrink, M., N. Aye-Han, and J. Zhang. (2010) Visualization of JNK activity dynamics with a genetically encoded fluorescent biosensor. Proc. Natl. Acad. Sci. USA 107:5459-5464.
Ananthanarayanan, B., Q. Ni, and J. Zhang. (2005) 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.
DiPilato, L.M., X. Cheng, and J. Zhang. (2004) 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.
List of complete publications (pdf)