Contact
Education
PhD in Pharmacology, University of Pennsylvania School of Medicine
Academic Affiliation(s)
William S. McEllroy Professor and Chair, Department of Microbiology and Molecular Genetics
Member, Molecular Virology and Microbiology Graduate Program
Member, Molecular Genetics and Developmental Biology Graduate Program
Member, Molecular Pharmacology Graduate Program
Member, Program in Integrative Molecular Biology (PIMB) Graduate Program
Member, Infectious Diseases and Microbiology Graduate Program (GSPH)
Research
Src family kinases, Bcr-Abl and chronic myelogenous leukemia (CML). Selective targeting of Bcr-Abl, the tyrosine kinase oncoprotein responsible for CML, with the Abl kinase inhibitor imatinib is very effective in the chronic phase of the disease. However relapse due to drug resistance is an emerging problem resulting most often Bcr-Abl kinase domain mutations that impact drug binding. Clinical imatinib resistance also results from hyperactivation of Src-family kinases in CML cells. We discovered that Src-family kinases directly phosphorylate the Bcr-Abl SH3 domain, preventing the docking of this domain to its regulatory position on the SH2-kinase linker within the Abl kinase core. This finding suggests that Abl SH3:linker interactions persist in the context of Bcr-Abl, despite its constitutive kinase activity. This observation has led us to question whether enhanced SH3:linker interaction can allosterically inhibit both wild-type and drug-resistant forms of Bcr-Abl. To this end, we have developed Abl kinase variants in which SH3:linker interaction has been enhanced, and found that they show dramatically reduced kinase activity and enhanced inhibitor sensitivity. We are currently developing screening assays to identify small molecules that induce this same allosteric effect as a new approach to selective inhibition of Bcr-Abl.
The c-Fes tyrosine kinase as a drug target in cancer. The c-fes proto-oncogene encodes a non-receptor tyrosine kinase with unique regulatory features, including N-terminal F-BAR and coiled-coil domains. Fes kinase activity is normally tightly controlled and contributes to the growth and differentiation of hematopoietic, endothelial and neuronal cells. Unscheduled activation of Fes contributes to the development of several forms of cancer, including acute myeloid leukemia and multiple myeloma. We are actively pursuing discovery of small molecule inhibitors selective for c-Fes, which will be useful tools to explore the role of this kinase in both normal biology and cancer.
Lab Personnel
Lori Emert-Sedlak - Research Assistant Professor
Patti George - Faculty Researcher
Prerna Grover - Graduate Student
Sabine Hellwig - Research Associate
Jerrod A. Poe - Postdoctoral Associate
Sherry Shu - Postdoctoral Associate
Sreya Tarafdar - Graduate Student
Mark Weir - Graduate Student
Jielu Zhao - Postdoctoral Associate
Publications
Panjarian S, Iacob R. E, Chen S, Wales T. E, Engen J. R, and Smithgall T. E. Enhanced SH3/Linker Interaction Overcomes Abl Kinase Activation by Gatekeeper and Myristic Acid Binding Pocket Mutations and Increases Sensitivity to Small Molecule Inhibitors. J Biol Chem. 288: 6116-6129. | View Abstract
Panjarian S, Iacob R. E, Chen S, Engen J. R, and Smithgall T. E. Structure and dynamic regulation of abl kinases. J Biol Chem. 288: 5443-5450. | View Abstract
Emert-Sedlak L. A, Narute P, Shu S. T, Poe J. A, Shi H, Yanamala N, Alvarado J. J, Lazo J. S, Yeh J. I, Johnston P. A, and Smithgall T. E. Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Chem Biol. 20: 82-91. | View Abstract
Narute P. S. and Smithgall T. E. Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner. PLoS One. 7: e32561. | View Abstract
Hellwig S, Miduturu C. V, Kanda S, Zhang J, Filippakopoulos P, Salah E, Deng X, Choi H. G, Zhou W, Hur W, Knapp S, Gray N. S, and Smithgall T. E. Small-molecule inhibitors of the c-Fes protein-tyrosine kinase. Chem Biol. 19: 529-540. | View Abstract
Pene-Dumitrescu T. and Smithgall T. E. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 285: 21446-21457. | View Abstract
Meyn M. A., 3rd. and Smithgall T. E. Chemical genetics identifies c-Src as an activator of primitive ectoderm formation in murine embryonic stem cells. Sci Signal. 2: ra64. | View Abstract