Structural basis of Jak3-mediated interleukin-2 family signal transduction

Summary

Principal Investigator: Titus J Boggon
Affiliation: Yale University
Country: USA
Abstract: Proper function of cytokine signaling pathways is critical for immunoregulation, hematopoiesis, and cytokine- directed inflammation and growth. Most signals from type I and type II cytokines are mediated by the Janus kinase (Jak) family of non-receptor tyrosine kinases. Our plan is to discover the molecular basis for cytoplasmic signal transduction from the interleukin-2 family cytokines through Jak3. We will use structural biology to provide the first description of Jak interactions with cytokine receptor cytoplasmic tails, to investigate Jak kinase domain specificity, regulation and inhibition, and to describe the role of the PERM domain in kinase activation. Specifically, we will focus our work in three distinct areas. In Aim 1 we will determine crystal structures of the kinase domain of Jak3. Modulation of the immune response by suppression of Jak3 kinase activity has clinical precedence. We will determine the mode of binding for Jak3 tyrosine kinase inhibitors and aid the discovery of further inhibitors that may be useful as immunomodulatory and anti-proliferative therapies. We will also discover the mode of Jak3 binding to a Jak3-preferred substrate and discover the inactive conformation of the kinase. In Aim 2, we will determine the structural basis for the almost exclusive Jak3 association with the interleukin-2 receptor gamma subunit. For this we will solve crystal structures that describe the interaction of the Jak3 PERM domain with peptides from the interleukin-2 receptor gamma subunit and investigate their binding affinities. Finally, following our structural studies on the kinase and PERM domains of Jak3, in Aim 3 we will determine the structural basis for Jak3 kinase domain association with the Jak3 FERM domain. We will also test the role of this interface as a suggested Jak3 active state stabilizing mechanism. These studies will directly impact healthcare stimulating the development of improved immunomodulatory and anti-proliferative therapies and by enhancing molecular-level understanding of cytokine signaling pathways.
Funding Period: 2007-06-01 - 2012-05-31
more information: NIH RePORT

Top Publications

  1. pmc Structure and clinical relevance of the epidermal growth factor receptor in human cancer
    Amit Kumar
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar St, SHM B 316A, New Haven, CT 06520 8066, USA
    J Clin Oncol 26:1742-51. 2008
  2. pmc JAK3: a two-faced player in hematological disorders
    Melanie G Cornejo
    Harvard Medical School, Boston, MA 02115, USA
    Int J Biochem Cell Biol 41:2376-9. 2009
  3. pmc Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells
    Jae Hyun Bae
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 107:2866-71. 2010

Detail Information

Publications3

  1. pmc Structure and clinical relevance of the epidermal growth factor receptor in human cancer
    Amit Kumar
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar St, SHM B 316A, New Haven, CT 06520 8066, USA
    J Clin Oncol 26:1742-51. 2008
    ..We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated...
  2. pmc JAK3: a two-faced player in hematological disorders
    Melanie G Cornejo
    Harvard Medical School, Boston, MA 02115, USA
    Int J Biochem Cell Biol 41:2376-9. 2009
    ....
  3. pmc Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells
    Jae Hyun Bae
    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 107:2866-71. 2010
    ..The experiments presented in this report provide the molecular basis underlying the control of transphosphorylation of FGF receptors and other receptor tyrosine kinases...