We are interested in understanding the mechanisms of normal and altered regulation of human protein kinases. Our primary focus is on the Janus kinase family. We also maintain collaborations that investigate dysreguation of other kinases in cancer, including the EGFR tyrosine kinase. Janus Kinases The Janus(Jak) family of tyrosine kinases is a central mediator of many signaling pathways and is the major kinase family associated with cytokine signal transduction. There are four vertebrate Jak family members (Jak1, Jak2, Jak3 and Tyk2), each comprising four regions, a carboxy-terminal kinase, pseudokinase, SH2-like and an amino-terminal FERM domain. Cytokines and growth factors function through interaction with specific cell surface receptors that transduce the extracellular signal. The ensuing signaling cascade is mediated by specific phosphorylation events, resulting in transcriptional regulation. The Jak/STAT (Signal transducers and activators of transcription) pathway is the primary means of this signal mediation from cytokine receptors. The Jak/STAT pathway is altered in multiple diseases including the classical myeloproliferative disorders and in severe combined immunodeficiency. Our goal is to define, crystallographically, atomic resolution structures of the Janus kinase family of proteins and to use structure to reveal mechanisms of signal transduction through, and regulation of, the Jak kinases. We also plan on providing a structural foundation for development of novel immunomodulatory and anti-cancer drugs. Our laboratory collaborates on structure-based functional studies of protein kinases with the Gilliland, Halmos, Ma and Chen laboratories.