Structural Biology of Cell Signaling and Cancer
We use biochemical and structural methods (primarily X-ray crystallography) to study the structure and regulation of tyrosine kinases that are important in cancer. We are especially interested in understanding how cancer-causing mutations lead to loss of normal kinase regulation, and in using structural approaches to develop new anticancer drugs. Active areas of investigation include: (1) the structure and regulation of Jak-family kinases and their interactions with cytokine receptors, (2) lung cancer-derived mutations in the epidermal growth factor receptor (EGFR), (3) the structural biology of focal adhesion kinase (FAK), and (4) formin proteins and their role in assembling the actin cytoskeleton.
Jak family kinases are central mediators of cytokine signaling, and mutations and chromosomal translocations of Jaks lead to hematopoietic cancers. In particular, the V617F mutation in Jak2 causes myeloproliferative neoplasms. We have recently discovered how this mutation alters the conformation of a regulatory “pseudokinase” domain that is unique to Jak-family members, and we are working to understand how this signal is in turn transmitted to the kinase domain. A long-term goal is to discover inhibitors that specifically inhibit this mutant, without interfering with the function of other Jaks in normal cells. We are also working to understand how the erythropoietin receptor binds and regulates Jak2.
Mutations in the EGFR tyrosine kinase are a common cause of non-small cell lung cancer. Our structural and biochemical studies have shown how several of these mutations activate the kinase and simultaneously alter its sensitivity to inhibitors such as the drug erlotinib. We have extensively characterized the drug-resistant EGFR T790M mutant and with our collaborators at the Dana-Farber, we developed a novel inhibitor WZ4002 that is highly active against this mutant.
Because FAK signaling is critical for cell migration, it is thought to play an important role in the invasiveness and metastasis of human tumors. We determined the structure of FAK, which shows how its catalytic activity is regulated by its N-terminal “FERM” region. We are currently studying how this inhibitory interaction of the FERM domain is released to activate FAK. Additionally, to facilitate development of drugs specifically targeting FAK, we have analyzed the structure of FAK in complex with a number of inhibitors.
Finally, in addition to tyrosine kinases, the laboratory studies formins, a large family of proteins that direct the assembly of the actin cytoskeleton in response to activation by Rho family GTPases. We discovered the unique “tethered-dimer” architecture of the formin FH2 domain, which is especially adapted for its role in directly assembling linear actin filaments. Additionally we are studying formin regulation and interactions with accessory proteins that allow formins to build distinct actin structures for particular cellular processes.