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Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades

Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts,¹ Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, Yale University, New Haven, Connecticut²

Received 2 December 2004/ Returned for modification 7 January 2005/ Accepted 3 February 2005

Mixed-lineage protein kinase 3 (MLK3) is a member of the mitogen-activated protein (MAP) kinase kinase kinase group that has been implicated in multiple signaling cascades, including the NF-B pathway and the extracellular signal-regulated kinase, c-Jun NH₂-terminal kinase (JNK), and p38 MAP kinase pathways. Here, we examined the effect of targeted disruption of the murine Mlk3 gene. Mlk3^–/– mice were found to be viable and healthy. Primary embryonic fibroblasts prepared from these mice exhibited no major signaling defects. However, we did find that MLK3 deficiency caused a selective reduction in tumor necrosis factor (TNF)-stimulated JNK activation. Together, these data demonstrate that MLK3 contributes to the TNF signaling pathway that activates JNK.

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