Letter abstract

Nature Cell Biology 6, 770 - 776 (2004)
Published online: 18 July 2004 | doi:10.1038/ncb1152

MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation

Deborah N. Chadee1 & John M. Kyriakis1

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The ERK group of mitogen-activated protein kinases (MAPKs) is essential for cell proliferation stimulated by mitogens, oncogenic ras and raf (ref. 1). All MAPKs are activated by MAP3K/MEK/MAPK core pathways1 and the Raf proto-oncoproteins, especially B-Raf, are ERK-specific MAP3Ks (refs 1–3). Mixed lineage kinase-3 (MLK3) is a MAP3K that was thought to be a cytokine-activated, and comparatively selective, regulator of the JNK group of MAPKs (refs 1, 4–6). Here we report that silencing of mlk3 by RNAi suppressed mitogen and cytokine activation not only of JNK but of ERK and p38 as well. Silencing mlk3 also blocked mitogen-stimulated phosphorylation of B-Raf at Thr 598 and Ser 601, a step required for B-Raf activation7, 8. Furthermore, silencing mlk3 prevented serum-stimulated cell proliferation and the proliferation of tumour cells bearing either oncogenic Ki-Ras or loss-of-function neurofibromatosis-1 (NF1) or NF2 mutations. The proliferation of tumour cells containing activating B-raf or raf-1 mutations was unaffected by silencing mlk3. Our results define an unexpected role for MLK3 in mitogen regulation of B-Raf, ERK and cell proliferation.

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  1. The Molecular Cardiology Research Institute, Department of Medicine, Tufts-New England Medical Center and The Department of Medicine, Tufts University School of Medicine, 750 Washington Street, Box 8486, Boston, MA 02111, USA.

Correspondence to: John M. Kyriakis1 e-mail: jkyriakis@tufts-nemc.org



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