A novel signal transduction pathway has recently been revealed in the interferon system. In this pathway, the regulatory subunits of a transcription factor, ISGF3, are directly phosphorylated by a tyrosine kinase(s) which is induced by interferon-alpha. Studies from this laboratory have shown that these regulatory subunits (p113 and p9l/84, ISGF3alpha) contain SH2 and SH3 domains, and that tyrosine phosphorylation is required for their activation. This is the first example of a transcription factor which can be activated directly by a tyrosine kinase. In this application, we propose investigating the detailed mechanism of activation of ISGF3. We will focus on the functional effects of tyrosine phosphorylation of ISGF3alpha proteins and the roles of the SH2 and SH3 domains in mediating interferon-alpha-induced signal transduction. We will further determine whether tyrosine kinase Tyk2 directly phosphorylates ISGF3alpha proteins. The nuclear localization signal (NLS), domains required for interactions between ISGF3 proteins and the stoichiometry of ISGF3 will also be characterized. We will determine whether this observed tyrosine phosphorylation unmasks the putative leucine zipper-like domains and NLS, resulting in complex formation and translocation of ISGF3alpha proteins to the nucleus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034522-06
Application #
2633530
Study Section
Molecular Biology Study Section (MBY)
Project Start
1994-01-01
Project End
1998-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Moh, Akira; Zhang, Wenjun; Yu, Sidney et al. (2008) STAT3 sensitizes insulin signaling by negatively regulating glycogen synthase kinase-3 beta. Diabetes 57:1227-35
Moh, Akira; Iwamoto, Yoshiki; Chai, Gui-Xuan et al. (2007) Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery. Lab Invest 87:1018-28
Zhang, Xuchen; Shan, Peiying; Jiang, Ge et al. (2006) Endothelial STAT3 is essential for the protective effects of HO-1 in oxidant-induced lung injury. FASEB J 20:2156-8
Zhang, Xuchen; Shan, Peiying; Alam, Jawed et al. (2005) Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J Biol Chem 280:8714-21
Gao, Qian; Wolfgang, Michael J; Neschen, Susanne et al. (2004) Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci U S A 101:4661-6
Laouar, Yasmina; Welte, Thomas; Fu, Xin-Yuan et al. (2003) STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19:903-12
Kano, Arihiro; Wolfgang, Michael J; Gao, Qian et al. (2003) Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. J Exp Med 198:1517-25
Jacoby, Jorg J; Kalinowski, April; Liu, Mu-Gen et al. (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A 100:12929-34
Welte, Thomas; Zhang, Samuel S M; Wang, Tian et al. (2003) STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A 100:1879-84
Xie, B; Zhao, J; Kitagawa, M et al. (2001) Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion. J Biol Chem 276:19512-23

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