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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 pathways 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 activation. 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. [ABSTRACT FROM AUTHOR]

Reports on the discovery of a unique subfamily of extracellularly regulated kinase enzymes with the molecular cloning of the c-Jun N-terminal kinase p54. Predicted amino-acid sequences of cDNAs for four p54 clones; Activation of associated kinases; Phosphorylation of c-Jun in situ in response to heat shock; Mitogenic and stress signalling pathways in c-Jun phosphorylation.

Explores the possibility that Raf-1 kinases lie upstream from mitogen-activated protein (MAP) kinases in the mitogen signally cascade. Reports that MAP kinase-kinase (MAP-K) as well as Erk1 adn 2 are constitutively active in v-raf-transformed cells.

Focuses on the balance of the molecular survival. Significance of the immune systems of the tumor-necrosis factor; Coordination of the immune systems and the inflammatory response to infection; Identification of the receptors on bone morphogenetic proteins activation.