Metabolic stress signaling mediated by mixed-lineage kinases
Howard Hughes Medical Institute; Program in Molecular Medicine
Animals; Embryo, Mammalian; Fatty Acids, Nonesterified; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 3; MAP Kinase Kinase 7; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins; Protein Kinase C; *Signal Transduction
Life Sciences | Medicine and Health Sciences
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.
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Citation: Mol Cell. 2007 Aug 3;27(3):498-508. Link to article on publisher's site