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

Abstract

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-κB 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.

ACKNOWLEDGMENTS

We thank Stephen Jones for blastocyst injections; Linda Evangelista for ES cell culture; Tammy Barrett, Judith Reilly, Vicky Benoit, and Jennifer Ayala for expert technical assistance; and Kathy Gemme for administrative assistance.

These studies were supported by a grant from the National Institutes of Health and by the Diabetes and Endocrinology Research Center (DERC) of the University of Massachusetts (NIH/NIDDK). R.A.F. and R.J.D. are investigators of the Howard Hughes Medical Institute.