Genomes and Genes
Structural Studies of the Pseudokinase Domain of Jak2.
Principal Investigator: Stevan R Hubbard
Abstract: DESCRIPTION (provided by applicant): Janus kinases (Jaks), members of the non-receptor protein tyrosine kinase family, are key components of signaling pathways in cells of the immune system and in hematopoietic cells. Jaks are associated with the cytoplasmic domains of cytokine receptors and, upon cytokine-mediated receptor dimerization, undergo trans- autophosphorylation on tyrosine residues, which stimulates their tyrosine kinase activity. Activated Jaks phosphorylate STATs (signal transducers and activators of transcription), which translocate to the nucleus and serve as transcriptional activators. There are four mammalian members of the Jak family (Jak1-3 and Tyk2) which possess four domains in common: an N-terminal FERM domain, an SH2-like domain, a pseudokinase domain, and a tyrosine kinase domain. Extensive biochemical data, as well as gain-of-function mutations that cause myeloproliferative diseases/cancers, have implicated the pseudokinase domain of Jaks as crucial for maintaining a low basal level of tyrosine kinase activity. The goal of this proposal is to understand the structural/molecular mechanisms by which the pseudokinase domain negatively regulates the tyrosine kinase activity of Jak2. To achieve this goal, x-ray crystallography will be employed to determine the three-dimensional structures of the pseudokinase domain and the tandem pseudokinase and tyrosine kinase domains.
Funding Period: 2012-03-15 - 2015-02-28
more information: NIH RePORT
- Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617FRajintha M Bandaranayake
Structural Biology Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, USA
Nat Struct Mol Biol 19:754-9. 2012..The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs...
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School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
Biochem Soc Trans 41:1002-7. 2013..These results provide structural and functional insights into the normal and pathogenic function of the JH2 domain of JAK2. ..
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