Metabolic stress signaling mediated by mixed-lineage kinases
Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
Mol Cell. 2007 Aug 3;27(3):498-508. Link to article on publisher's site
Jaeschke A, Davis RJ. (2007). Metabolic stress signaling mediated by mixed-lineage kinases. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.molcel.2007.07.008. Retrieved from https://escholarship.umassmed.edu/oapubs/1326