Greater Philadelphia Professor of Biological Sciences
Publications | Research | Faculty
Background:
David Shalloway is the Greater Philadelphia Professor in the Department of Molecular Biology and Genetics. After receiving his Ph.D. in theoretical physics at the Massachusetts Institute of Technology in 1975, he became a Research Associate in the Newman Laboratory of Nuclear Studies at Cornell developing renormalization group methods in quantum field theory. In 1977 he switched research directions to focus on the molecular basis of oncogene-mediated carcinogenesis. The transition was supported by Postdoctoral Fellowships from the National Institutes of Health and the American Cancer Society at the Dana-Farber Cancer Institute of the Harvard Medical School. From 1982-90, he was on the faculty of the Department of Molecular and Cell Biology at The Pennsylvania State University conducting research on src and other oncogenes and on computer applications in molecular biology. From 1988-89 he was Visiting Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco Medical School, developing a new theoretical approach to the protein folding problem. Dr. Shalloway has received an American Cancer Society Junior Faculty Research Award, a National Institutes of Health Research Career Development Award, and has served on a number of National Institutes of Health grant review committees. He has been at Cornell since 1990.
Courses Taught:
BioBM838 - Methods and Logic in Biochemistry, Molecular and Cell Biology II
BioBM700 - Statistics for Experimental Biochemistry, Molecular and Cell Biology (specified years)
Links:
- QMOL An OpenGL based molecular viewer for Windows 95/NT/00 and X Windows (free software)
- PrestoPlot A 2D plotting tool for Win32 Platforms (free software)
- MATILDA: Recombinant DNA Cloning Software
Our research is focused in two areas:
- interations of Src and Protein Tyrosine Phosphatase a in Cancer
- theoretical prediction of protein conformational changes.
Interations of Src and Protein Tyrosine Phosphatase a in Cancer
Functional analyses of the protein products of proto-oncogenes have provided excellent starting points for studying the molecular basis of carcinogenesis. We are studying the Src proto-oncoprotein and related signal-transduction proteins. It is a paradigm for the largest class of proto-oncogene products--the cytoplasmic protein-tyrosine kinases. Src's activity is elevated in more than half of human breast and colon cancers by unknown means. We and others have shown that Src is regulated by a sophisticated network of phosphorylation and dephosphorylation reactions, and we have recently shown that a key upstream regulator is Protein Tyrosine Phosphatase a . Our recent studies have revealed that PTP a and Src interact via an intricate biochemical “dance” (e.g., see figure) that is controlled by multiple phosphorylations, and a major focus of our research is to gain further insight into the regulation of this process. Moreover, our most recent work shows that inhibiting PTP a activity specifically downregulates Src and induces apoptosis in human breast and colon cancer cells, but not in normal cells. This suggests that PTP a is involved in the abnormal activation of Src in these cancers, and that PTP a may be a highly specific, and hence very useful, target for chemotherapy. Current and future insights into the mechanism of the PTP a -Src interaction can provide valuable insights for the design of highly specific drugs.
The ability to computationally predict the changes induced in the 3-dimensional structures of proteins and ligands due to mutations, post-translational modifications, and/or protein-ligand binding will have important applications in structure-based drug design and biotechnology. For example, the conformational changes that occur when enzymes and substrates interact greatly affect their binding energies and must be understood for rational design of improved inhibitors. Existing theoretical methods are inadequate for most practical applications. We are developing improved computational tools for this purpose. We are focussing on the use of methods from statistical physics to dissect the behavior of these complex systems according to size scale. Computer algorithms for "hierarchical macrostate analysis" are being developed towards the goal of eventual application to physiologically important problems.
Theoretical group:
Saleh El-Mohammed
Steven Fairchild
Experimental group:
Ross Resnick
Xin-Min Zheng
Barbara Tremper-Wells
Recent publications (including theoretical papers not listed in PubMed)
Click here to view Dr. Shalloway's PubMed listings.
Church, B. W., A. Ulitsky, and D. Shalloway (1999) Macrostate dissection of thermodynamic Monte Carlo integrals. Adv. Chem. Phys. 105:273-310.
Laird, A. D., D. K. Morrison, and D. Shalloway (1999) Characterization of Raf-1 activation in mitosis. J. Biol. Chem. 274:4430-4439.
Gans, J. and D. Shalloway (2000) Shadow mass and the relationship between velocity and momentum in symplectic numerical integration, Phys. Rev. E 61: 4587-4592.
Zheng, X.-M., R. Resnick, and D. Shalloway (2000) A phosphotyrosine-displacement mechanism for activation of Src by PTP a.? EMBO J. 19:964-978.
Elber, R. and D. Shalloway (2000) Temperature-dependent reaction coordinates. J. Chem. Phys. 112:5539-5545.
Shalloway, D. (2001) Packet annealing. In Encyclopedia of Global Optimization, C.A. Floudas and P.M. Pardalos, eds. (Kluwer Academic, Norwell, MA).
Taylor, S.J., R. Resnick and D. Shalloway (2001) Non-radioactive determination of Ras-GTP levels using ARIA, Meth. Enzymol. 333:333-342.
Church, B.W. and D. Shalloway (2001) Top-down free-energy minimization on protein potential energy landscapes. Proc. Natl. Acad. Sci. USA 98: 6098-6103.
Gans, J.D. and D. Shalloway (2001) Qmol: a program for molecular visualization on Windows-based PCs. J. Molec. Graphics Model 19:557-559.
Zheng, X.-M., and D. Shalloway (2001) Two mechanisms activate PTP a during mitosis. EMBO J. 20:6037-6049.
Zheng, X.-M, R.J. Resnick, and D. Shalloway (2002) Mitotic activation of PTP a and regulation of its Src-mediated transforming activity by its sites of PKC phosphorylation. J. Biol. Chem. 277:21922-219299.
Hong, W., R.-J. Resnick, C. Rakowski, D. Shalloway, S.J. Taylor, and G. A. Blobel (2002) Physical and functional interaction between the transcriptional cofactor CBP and the KH domain protein Sam68. Mol. Canc. Res. 1:48-55.
Oresic, M., M. Dehn, D. Korenblum, and D. Shalloway (2003) Tracing synonymous codon-secondary structure correlations through evolution. J. Mol. Evol. 56:473-484.
Korenblum, D. and D. Shalloway (2003) Macrostate data clustering. Phys. Rev. E. 67:056704.
Taylor, S.J., R. J. Resnick and D. Shalloway (2004) Sam68 exerts separable effects on cell cycle progression and apoptosis. BMC Cell Biol. 5:5.