Structural Studies of the Pseudokinase Domain of Jak2.

Summary

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

Top Publications

  1. pmc Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F
    Rajintha 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
  2. ncbi New insights into the structure and function of the pseudokinase domain in JAK2
    Olli Silvennoinen
    School of Medicine and Institute of Biomedical Technology, University of Tampere, 33014 Tampere, Finland
    Biochem Soc Trans 41:1002-7. 2013

Research Grants

  1. Novel therapeutic targets for Leukemia in Elderly
    Holly Martin; Fiscal Year: 2013
  2. Role of Vav and Rac in KIT oncogenesis
    Reuben Kapur; Fiscal Year: 2013
  3. Nucleosome Reorganizing/Remodeling Complexes
    Christopher P Hill; Fiscal Year: 2013
  4. Structure and regulation of beta-catenin during cell-cell adhesion
    JEFFREY D HARDIN; Fiscal Year: 2013
  5. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F
    Rajintha 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...
  2. ncbi New insights into the structure and function of the pseudokinase domain in JAK2
    Olli Silvennoinen
    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. ..

Research Grants30

  1. Novel therapeutic targets for Leukemia in Elderly
    Holly Martin; Fiscal Year: 2013
    ..I expect the results of these studies to enhance our understanding of the mechanism of KITD816V-induced transformation, and potentially provide novel therapeutic targets for oncogenic KIT bearing neoplasms. ..
  2. Role of Vav and Rac in KIT oncogenesis
    Reuben Kapur; Fiscal Year: 2013
    ..abstract_text> ..
  3. Nucleosome Reorganizing/Remodeling Complexes
    Christopher P Hill; Fiscal Year: 2013
    ..We aim to advance understanding of function by a combination of determining relevant three-dimensional structures, biochemistry, and genetic analysis. ..
  4. Structure and regulation of beta-catenin during cell-cell adhesion
    JEFFREY D HARDIN; Fiscal Year: 2013
    ..BAR-1 binds POP-1/Tcf with high affinity, and retains Helix C. We will test the role of Helix C using domain-swap experiments between HMP-2 and BAR-1, and assessing Tcf binding in vitro and coactivator functions in vivo. ..
  5. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..