Metabolic stress signaling mediated by mixed-lineage kinases

UMMS Affiliation

Program in Molecular Medicine

Publication Date


Document Type



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

Journal/Book/Conference Title

Molecular cell

Related Resources

Link to Article in PubMed

PubMed ID