Metabolic Stress Signaling Mediated by Mixed-Lineage Kinases

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• 作者：Anja Jaeschke ; Roger J. Davis
• 关键词：SIGNALING
• 刊名：Molecular Cell
• 出版年：2007
• 期刊代码：111_10972765
• 类别：bio
• 出版时间：3 August 2007
• 卷：27
• 期：3
• 页码：498-508
• 文件大小：956 K

摘要

Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH₂-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.