Journal
BIOCHEMICAL JOURNAL
Volume 388, Issue -, Pages 17-28Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20041236
Keywords
annexin II; interferon-gamma (IFN gamma); mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase kinas 4 (MEKK4); Pyk2; Src-homology-2-domain-containing phosphatase (SHP2); STAT1 (signal transducer and activator of transcription 1)
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Funding
- NIA NIH HHS [AG19710, R01 AG019710] Funding Source: Medline
- NIEHS NIH HHS [P30 ES006694, P30 ES06694, P42 ES004940, ES12007, R01 ES012007, P42 ES04940] Funding Source: Medline
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IFN gamma (interferon-gamma) binding to its cognate receptor results, through JAK (Janus kinase), in direct activation of receptor-bound STAT1 (signal transducer and activator of transcription 1), although there is evidence for additional activation of a MAPK (mitogen-activated protein kinase) pathway. In the present paper, we report IFN gamma-dependent activation of the MEKK4 (MAPK/extracellular-signal-regulated kinase kinase kinase 4) pathway in HaCaT human keratinocytes. MEKK4 is tyrosine-phosphorylated and the IFN gamma-dependent phosphorylation requires intracellular calcium. Calcium-dependent phosphorylation of MEKK4 is mediated by Pyk2. Moreover, MEKK4 and Pyk2 co-localize in an IFN gamma-dependent manner in the perinuclear region. Furthermore, the calcium-binding protein, annexin II, and the calcium-regulated kinase, Pyk2, co-immunoprecipitate with MEKK4 after treatment with IFN gamma. Immunofluorescence imaging of HaCaT cells shows an IFN gamma-dependent co-localization of annexin II with Pyk2 in the perinuclear region, suggesting that annexin II mediates the calcium-dependent regulation of Pyk2. Tyrosine phosphorylation of MEKK4 correlates with its activity to phosphorylate MKK6 (MAPK kinase 6) in vitro and subsequent p38 MAPK activation in an IFN gamma-dependent manner. Additional studies demonstrate that the SH2 (Src homology 2)-domain-containing tyrosine phosphatase SHP2 co-immunoprecipitates with MEKK4 in an IFN gamma-dependent manner and co-localizes with MEKK4 after IFN gamma stimulation in the perinuclear region in HaCaT cells. Furthermore, we provide evidence that SHP2 dephosphorylates MEKK4 and Pyk2, terminating the MEKK4-dependent branch of the IFN gamma signalling pathway.
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