STRUCTURAL BIOLOGY OF SIGNALING AND THE ACTIN CYTOSKELETON

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our subproject focuses in two inter-related areas  tyrosine kinases and formin family proteins and their regulators. We are working to understand the structure and regulation of tyrosine kinases, especially those that are dysregulated in cancer or are targets for anti-cancer drugs. We are studying focal adhesion kinase (FAK) in order to understand how it is regulated and to facilitate development of FAK-specific inhibitors. We are studying Jak-family kinases in order to understand their mechanism of association with cytokine receptors, how they are regulated by intramolecular interactions and how this regulation is disrupted in hematoproliferative disorders (such as polycythemia vera) in which Jak2 or Jak3 is mutated. Through our studies of the structure of EGFR kinase mutants, we hope elucidate mechanisms of oncogenic activation and drug resistance, and also to design inhibitors that are mutant-specific for use in the treatment of lung and other cancers that arise from EGFR mutations. In our investigations of formin proteins such as Daam1, mDia, and Bni1 we hope to learn how these molecules are regulated and how they function in actin assembly.