James K. Chen, Ph.D. (Assistant Professor)

Departmental Affiliation: Chemical and Systems Biology
Graduate Programs: Chemical and Systems Biology, Cancer Biology
Other Affiliations: Chemistry

Email: jameschen@stanford.edu
Website: http://chen.stanford.edu

Research Description:

Our laboratory investigates the molecular basis of embryonic development and oncogenesis through a multidisciplinary approach. We recently identified the cellular target of cyclopamine, a teratogen found in corn lilies, providing a long-awaited explanation for a mysterious outbreak of cyclopic sheep in the 1950s. Through genetic and biochemical methods, we have demonstrated that cyclopamine blocks an embryonic signaling cascade called the Hedgehog pathway by binding directly to Smoothened, a transmembrane protein that transduces the Hedgehog signal. Complementary studies in our laboratory have also identified Smoothened as the physiological target of another Hedgehog pathway-modulating small molecule, in this case a synthetic agonist discovered through high-throughput screens. These collective studies have yielded insights into the molecular mechanisms of Smoothened activation and suggest that Smoothened function is regulated by an endogenous small molecule. Furthermore, cyclopamine and other Smoothened inhibitors may constitute highly specific anti-tumor therapies, since aberrant Hedgehog signaling plays a critical role in the initiation and maintenance of numerous cancers. Building upon this foundation, mechanistic studies of Hedgehog signaling events downstream of Smoothened are now underway, employing both chemical and genetic strategies. Our laboratory is also pursuing related studies of Wnt signaling, another pathway intimately involved with embryonic development and the formation of certain tumors.

A second goal of our laboratory is the development of new methods for the study of vertebrate embryogenesis, using zebrafish as a model organism. The optical transparency and rapid development of zebrafish embryos have favored their use in studies of vertebrate patterning, and their susceptibility to chemical- or retrovirus-induced mutagenesis has led to the identification of several thousand mutant strains that will be invaluable tools for embryological research. However, reverse-genetic approaches to the study of zebrafish gene function have significantly lagged behind experimental methods available for other organisms that are less amenable to direct embryological observation. Bridging this gap is a major aim of our laboratory, and we are currently pursuing two independent strategies for the spatial and temporal control of gene expression in zebrafish. Both multidisciplinary approaches will enable the generation of zebrafish embryos with precisely tailored gene expression patterns, providing new opportunities for understanding vertebrate development at the molecular and systems levels.

Representative publications:

Esengil, H., Chang, V., Mich, J. K., and Chen, J. K. (2007) Small-molecule regulation of zebrafish gene expression. Nat. Chem. Biol. 3: 154-155.

Meloni, A. R., Fralish, G. B., Kelly, P., Salahpour, A., Chen, J. K., Wechsler-Reya, R. J., Lefkowitz, R. J. and Caron, M. G. (2006) Smoothened signal transduction is promoted by G-protein coupled receptor kinase 2. Mol. Cell. Biol. 26: 7550-7560.

Sinha, S. and Chen, J.K. (2006) Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol. 2: 29-30.

Chen, W., Ren, X., Nelson, C. D, Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., and Lefkowitz, R. J. (2004) Activity-dependent internalization of Smoothened mediated by beta-Arrestin 2 and GRK2. Science 306: 2257-2260.

Chen, J. K., Taipale, J., Young, K. E., Maiti, T., and Beachy, P. A. (2002) Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. U. S. A. 99: 14071-14076.

Chen, J. K., Taipale, J., Cooper, M. K., and Beachy, P. A. (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16: 2743-2748.

Berman, D. M., Karhadkar, S. S., Hallahan, A. R. Pritchard, J. I., Eberhart, C. G., Watkins, D. N., Chen, J. K., Cooper, M. K., Taipale, J., Olson, J. M., and Beachy, P. A. (2002) Medulloblastoma growth inhibition by Hedgehog pathway blockade. Science 297: 1559-1561.

Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., and Beachy, P. A. (2000) The effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406: 1005-1009.