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. The IPP complex The integrin-linked kinase, pinch, parvin (IPP) complex is ia hub in integrin-actin and integrin-signaling networks, and in mammalian systems complex formation precedes and is required for its correct targeting to adhesions. In addition, IPP complex formation protects its components from proteasomal degradation. The IPP complex has critical roles in anchorage-dependent cell growth and survival, cell cycle progression, epithelial to mesenchymal transition, cell motility, contractility and early development. The complex is also required for cardiac, vascular, brain, kidney, muscle, skin, platelet, chondrocyte and T cell function and plays important roles in tumor angiogenesis. We are interested in understanding the structural basis for IPP complex formation and the mechansisms of function. The CCM complex Cerebral cavernous malformation (CCM) has a prevalence of 0.1-0.5% in the human population and is an important cause of hemorrhagic stroke. Between 10 and 50% of CCM cases are associated with inherited autosomal-dominant mutations in three genes, CCM1, CCM2 and CCM3. These mutations are associated with destabilized vascular endothelial cell-cell interactions and CCM lesions. The molecular mechanisms for acquisition of CCM lesions are only beginning to be described, and the atomic-level interactions that become disrupted in CCM and their functional consequences have not yet been investigated. We are studying CCM3, CCM2 and CCM1 using a structure-directed functional approach. Polycystic Kidney Disease Polycystic kidney disease (PKD) is a systemic hereditary disease characterized by renal and hepatic cysts. There is no known cure for this disease and it results in end-stage renal failure in approximately 50% of affected individuals. Most cases (>95%) are caused by genetic mutations in either the Pkd1 or the Pkd2 gene, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Although mutations in these genes are causative for PKD, the molecular mechanisms that are altered by these mutations and the molecular events that result in clinical symptoms are still incompletely understood. There is little structural data to describe PC1, PC2, or their interactions with one another. Student projects We have multiple potential rotation projects. If you are interested in working with us please contact Titus