MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6.

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Citation

Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR, Lassam NJ

MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6.

EMBO J. 1996 Dec 16;15(24):7026-35.

PubMed ID
9003778 [ View in PubMed
]
Abstract

Mixed lineage kinase-3 (MLK-3) is a 97 kDa serine/threonine kinase with multiple interaction domains, including a Cdc42 binding motif, but unknown function. Cdc42 and the related small GTP binding protein Rac1 can activate the SAPK/JNK and p38/RK stress-responsive kinase cascades, suggesting that MLK-3 may have a role in upstream regulation of these pathways. In support of this role, we demonstrate that MLK-3 can specifically activate the SAPK/JNK and p38/RK pathways, but has no effect on the activation of ERKs. Immunoprecipitated MLK-3 catalyzed the phosphorylation of SEK1 in vitro, and co-transfected MLK-3 induced phosphorylation of SEK1 and MKK3 at sites required for activation, suggesting direct regulation of these protein kinases. Furthermore, interactions between MLK-3 and SEK and MLK-3 and MKK6 were observed in co-precipitation experiments. Finally, kinase-dead mutants of MLK-3 blocked activation of the SAPK pathway by a newly identified mammalian analog of Ste20, germinal center kinase, but not by MEKK, suggesting that MLK-3 functions to activate the SAPK/JNK and p38/RK cascades in response to stimuli transduced by Ste20-like kinases.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Mitogen-activated protein kinase kinase kinase 11Q16584Details
Dual specificity mitogen-activated protein kinase kinase 4P45985Details