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    Mol Cell. 2007 Aug 3;27(3):498-508.

    Metabolic stress signaling mediated by mixed-lineage kinases.

    Jaeschke A, Davis RJ.

    Source

    Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.

    Abstract

    Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH(2)-terminal kinase (JNK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)-dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.

    PMID:
    17679097
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC1986670
    Free PMC Article

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