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Protein tyrosine kinase Pyk2 mediates the Jak‐dependent activation of MAPK and Stat1 in IFN‐γ, but not IFN‐α, signaling
Author(s) -
Takaoka Akinori,
Tanaka Nobuyuki,
Mitani Yukiko,
Miyazaki Tadaaki,
Fujii Hodaka,
Sato Mitsuharu,
Kovarik Pavel,
Decker Thomas,
Schlessinger Joseph,
Taniguchi Tadatsugu
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.9.2480
Subject(s) - biology , tyrosine kinase 2 , janus kinase , microbiology and biotechnology , stat1 , signal transduction , tyrosine kinase , jak stat signaling pathway , mapk/erk pathway , cancer research , tyrosine , protein tyrosine phosphatase , proto oncogene tyrosine protein kinase src , receptor tyrosine kinase , janus kinase 1 , platelet derived growth factor receptor , biochemistry , receptor , growth factor
Two distinct types of interferon, IFN‐α/β and IFN‐γ, commonly exhibit antiviral activities by transmitting signals to the interior of the cell via their homologous receptors. Receptor stimulation results in the activation of distinct combinations of Janus family protein tyrosine kinases (Jak PTKs); Jak1/Tyk2 and Jak1/Jak2 for IFN‐α/β and IFN‐γ, respectively. Jak PTK activation by these IFNs is commonly followed by tyrosine phosphorylation of the transcription factor Stat1 at Y701, which is essential for dimerization, translocation to the nucleus and DNA‐binding activity. To gain full transcriptional activity, Stat1 also requires serine phosphorylation at S727. In this paper we demonstrate that Pyk2, which belongs to another PTK family, is critical for the Jak‐mediated MAPK and Stat1 activation by IFN‐γ, but not IFN‐α. Pyk2 is selectively associated with Jak2 and activated by IFN‐γ. Overexpression of PKM, a dominant interfering form of Pyk2, in NIH 3T3 cells results in a strong inhibition of the IFN‐γ‐induced activation of Erk2, serine phosphorylation of Stat1 and Stat1‐dependent gene transcription. Finally, the antiviral action of IFN‐γ, but not IFN‐α, is severely impaired by PKM overexpression. Thus, the two types of IFN may utilize distinct Jak‐mediated Erk2, and possibly other MAPK activation pathways for their antiviral action.