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Smithgall Lab



Principal Investigator

Thomas E. Smithgall, PhD
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Location

533 Bridgeside Point II
450 Technology Dr.
Pittsburgh, PA 15219

Research Description

Smithgall, HIV Research in our laboratory is focused on non-receptor protein-tyrosine kinase structure, function, and inhibitor discovery. Specifically, we are interested in the Src, Abl and Fes kinase families, which were originally discovered in the context of avian transforming retrovirus many years ago. Since that time, normal human orthologs of these kinases have been identified and implicated in a wide variety of human diseases, ranging from cancer to HIV/AIDS. One important goal of our research program is to better understand the mechanisms of kinase regulation unique to each family. Structurally, these kinases are composed of a series of modular domains which assemble in unique ways to control kinase activity. For example, members of the Src family are composed of Src homology 2 (SH2) and SH3 domains, compact protein-protein interaction modules that work together to downregulate kinase activity. Our group has discovered that HIV encodes a protein that directly engages the SH3 domains of a subset of Src-family kinases, displacing SH3 from its regulatory position and causing kinase activation. Using high-throughput chemical library screening, we have identified selective inhibitors of this viral-host cell protein interaction that also interfere with HIV replication. Working with structural biologists, we are currently exploring the unique active conformations of Src kinases that result from interactions with HIV proteins. These studies will reveal high-resolution structural details essential to improving inhibitor potency and efficacy. Another example is Abl, best known in the context of Bcr-Abl, the chimeric oncogenic tyrosine kinase responsible for chronic myelogenous leukemia. Selective inhibitors of this kinase have been remarkably effective in the treatment of this form of cancer. Bcr-Abl inhibitors selectivity recognize and trap a unique, inactive kinase domain conformation. Like Src-family kinases, Bcr-Abl also has SH3 and SH2 modules important for kinase regulation. We are very interested in the discovery of small molecules that enhance this natural regulatory mechanism. The Fes-related kinases also share homology with Abl and Src in that they have SH2 and kinase domains. However, these kinases also possess a unique N-terminal region with coiled-coil homology domains. Coiled-coils are helical structures that hold proteins together, and are responsible the oligomeric nature of Fes in vivo. We have observed that the coiled-coils are also critical to downregulation of kinase activity. Unlike Src and Abl, no pharmacological inhibitors of c-Fes have been reported. To fill this void, we recently identified a variety of compounds with potent activity against c-Fes. Using these inhibitors, we demonstrated for the first time that Fes has an essential role in the differentiation of macrophages to osteoclasts, making it a possible drug target in osteoporosis, multiple myeloma, and tumor angiogenesis. More generally, our research program seeks to exploit the novel regulatory features of each of these kinase families to develop new classes of selective kinase inhibitors. Such compounds represent valuable probes to explore kinase function in normal cellular physiology and in disease.

Members:

Heather Rust, Postdoctoral Associate                            

Haibin Shi, Research Assistant Professor

Ryan Staudt, Graduate Student

Li Chen, Research Specialist

Julie Reese, Research Specialist

Manish Aryal, Graduate Student 

Members

Jerrod A. Poe -Research Assistant Professor
John J. Alvarado -Research Assistant Professor
Kindra Whitlatch -Graduate Student
Lori Emert-Sedlak -Research Assistant Professor
Mark Weir -Postdoctoral Associate
Ravi K. Patel -Graduate Student
Sherry Shu -Research Assistant Professor