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Thomas E. Smithgall, PhD

Dr. Tom Smithgall


Fax: 412-624-8997
530 Bridgeside Point II
450 Technology Drive


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)


Src family kinases, HIV Nef, and AIDS.  Our group continues to explore the interaction of Src-family kinases with Nef, an HIV accessory protein essential for AIDS progression.  Nef binds directly to the SH3 domains of several Src-family members found in HIV target cells (Hck, Lyn and c-Src), leading to constitutive kinase activation.  In collaboration with the University of Pittsburgh Drug Discovery Institute, we are actively running in vitro and cell-based high-throughput screens of chemical libraries to identify selective inhibitors of the Nef:Hck complex. We have identified several new classes of Nef-dependent compounds with potent anti-HIV activity in vitro. These compounds represent exciting new tools for exploring the role of Nef-mediated Src-family kinase signaling in HIV pathogenesis as well as leads for anti-HIV drug development.  We are also exploring the structural biology of Nef in complex with Src family kinases and in the presence of small molecule inhibitors.

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


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