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 defined regions, a carboxy-terminal kinase, pseudokinase, SH2-like and an amino-terminal FERM domain. We solved the first Jak family crystal structure, that of the kinase domain of Jak3 (Boggon et al.). Cytokines and growth factors function through interaction with specific cell surface receptors that rapidly 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. Janus kinases are dysregulated in cancer: Transforming translocations are seen in leukemias between the oligomerization domain of Tel transcription factor and the catalytic domain of Jak2. Other malignancies have been shown to inappropriately activate Janus kinases, such as cancers that express oncogenic tyrosine kinases (Verma et al.). Also, certain myeloproliferative disorders demonstrate dysregulation of Jak2 due to an acquired valine to phenylanaline mutation (Levine et al.). Janus kinases are dysregulated in SCID: Deficiency of catalytically active Jak3 or disruption of the Jak3 interaction with the IL-2 receptor common-gamma chain results in severe combined immunodeficiency. This disease is characterized by absence of T and natural killer cells and normal numbers of poorly functioning B cells (O'Shea et al.). Project aims: We are aiming to define, crystallographically, atomic resolution structures of the Janus kinase family of proteins. Our plan is 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.