Rewired ERK-JNK Signaling Pathways in Melanoma

Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun i...

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Bibliographic Details
Published in:Cancer cell 2007-05, Vol.11 (5), p.447-460
Main Authors: Lopez-Bergami, Pablo, Huang, Conway, Goydos, James S., Yip, Dana, Bar-Eli, Menashe, Herlyn, Meenhard, Smalley, Keiran S.M., Mahale, Alka, Eroshkin, Alexey, Aaronson, Stuart, Ronai, Ze'ev
Format: Article
Language:English
Subjects:
Base Sequence
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
MAP Kinase Kinase 4 - metabolism
MAP Kinase Signaling System
Melanoma - enzymology
Melanoma - pathology
Proto-Oncogene Proteins c-jun - metabolism
RNA, Small Interfering
SIGNALING
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Summary:Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2007.03.009