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National Institute of Environmental Health Sciences

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Publication Detail

Title: Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes.

Authors: Halfter, Ursula M; Derbyshire, Zachary E; Vaillancourt, Richard R

Published In Biochem J, (2005 May 15)

Abstract: IFNgamma (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 IFNgamma-dependent activation of the MEKK4 (MAPK/extracellular-signal-regulated kinase kinase kinase 4) pathway in HaCaT human keratinocytes. MEKK4 is tyrosine-phosphorylated and the IFNgamma-dependent phosphorylation requires intracellular calcium. Calcium-dependent phosphorylation of MEKK4 is mediated by Pyk2. Moreover, MEKK4 and Pyk2 co-localize in an IFNgamma-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 IFNgamma. Immunofluorescence imaging of HaCaT cells shows an IFNgamma-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 IFNgamma-dependent manner. Additional studies demonstrate that the SH2 (Src homology 2)-domain-containing tyrosine phosphatase SHP2 co-immunoprecipitates with MEKK4 in an IFNgamma-dependent manner and co-localizes with MEKK4 after IFNgamma 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 IFNgamma signalling pathway.

PubMed ID: 15601262 Exiting the NIEHS site

MeSH Terms: Animals; Annexin A2/chemistry; Annexin A2/physiology*; Calcium Signaling; Cell Line; Humans; Interferon-gamma/chemistry; Interferon-gamma/physiology*; Keratinocytes/physiology; MAP Kinase Kinase 6/physiology; MAP Kinase Kinase Kinase 4/chemistry; MAP Kinase Kinase Kinase 4/physiology*; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism*; Signal Transduction; Tyrosine

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