Department Affiliation: Primary: Biophysics and Biophysical Chemistry; Secondary: Pharmacology and Molecular Sciences
Degree: Ph.D., Stanford University
Telephone Number : 410-614-2534
Fax Number: 410-614-8839
E-mail address: firstname.lastname@example.org
School of Medicine Address: Hunterian 716, 725 N. Wolfe Street, Baltimore, MD 21205
Molecular studies of signal transduction.
We are interested in molecular mechanisms governing activity of signaling pathways in both normal and disease states. To address this problem, we express pathway components for biochemical, biophysical and X-ray crystallographic studies. Our current studies focus on two general areas: the Hedgehog pathway and signaling mediated by specific receptor tyrosine kinases, in particular members of the EGF receptor (EGFR/ErbB) family.
Hedgehog proteins play critical roles in tissue differentiation during animal development. Elaborate molecular mechanisms have evolved to regulate Hedgehog signaling in time and place, and defects in Hedgehog signaling underlie human disorders including birth defects to cancer. Our studies have elucidated the nature and strength of interactions between Hedgehog proteins and key pathway components, identified essential co-factors for specific interactions, and provided a molecular framework for understanding how these interactions contribute to the complex regulation of Hedgehog activity observed in living systems. We are currently extending our studies to additional pathway components.
The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases also mediates key signaling events during animal development, and abnormal signaling figures prominently in many human cancers. Our work uncovered an autoinhibited form of ErbB receptors in the absence of ligand that is shared by all human ErbB homologs except HER2, which has no known ligand. We have shown that HER2 instead adopts a constitutively active-like structure, which explains many of its unique properties and has influenced the development of drugs targeting HER2 in human cancers. We are currently investigating correlations between different ErbB conformations and signaling activity through structural and biophysical studies of additional ErbBs, related receptors, and designed receptor variants.
- Kim, M.-S., Saunders, A.M., Hamaoka, B.Y., Beachy, P.A., and Leahy, D.J. Structure of the protein core of the glypican Dally-like and localization of a region important for hedgehog signaling. Proc. Natl. Acad. Sci. USA, 2011, in press.
- Beachy, P.A., Hymowitz, S.G., Lazarus, R.A., Leahy, D.J., and Siebold, C. Interactions between Hedgehog proteins and their binding partners come into view. Genes and Development Sep 15;34(18):2001-2012, 2010. Pub Med Reference
- Kavran, J.M., Ward, M.D., Oladosu, O.O., Mulepati, S., and Leahy, D.J. All mammalian hedgehog proteins interact with cell-adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner. J. Biol. Chem. 285:24584-24590, 2010. Pub Med Reference
- Qiu, C., Tarrant, M.K., Boronina, T., Longo, P.A., Kavran, J.M., Cole, R.M., Cole, P.A., and Leahy, D.J. In Vitro enzymatic characterization of near full length EGFR in activated and inhibited states. Biochemistry 48:6624-6632, 2009. Pub Med Reference
- McLellan, J.S., Zheng, X., Hauk, G., Ghirlando, R., Beachy, P.A., and Leahy, D.J. The mode of Hedgehog binding to Ihog homologs is not conserved across different phyla. Nature Oct 16; 455:979-983, 2008. Pub Med Reference
- McLellan, J.S., Yao, S., Zheng, X., Geisbrecht, B.V., Ghirlando, R, Beachy, P.A.,and Leahy, D.J. Structure of a heparin-dependent complex of Hedgehog and Ihog. Proc Natl Acad Sci USA. Nov 14;103(46):17208-17213, 2006. Pub Med Reference
- Franklin, MC, Carey, K.D., Vajdos, F.F., Leahy, D.J., de Vos, A.M.,and Sliwkowski, M.X. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex, Cancer Cell 5(4):317-328, 2004. Pub Med Reference
Other graduate programs in which Dr. Leahy participates: