Metabolic stress signaling mediated by mixed-lineage kinases.
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.
Jaeschke
Anja
A
Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Davis
Roger J
RJ
D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000502:physiology; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D005230:Fatty Acids, Nonesterified; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C526295:Irs1 protein, mouse; C486650:Map3k9 protein, mouse; C482570:Map2k7 protein, mouse