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 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.
Lopez-Bergami
Pablo
P
Signal Transduction Program, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Huang
Conway
C
Goydos
James S
JS
Yip
Dana
D
Bar-Eli
Menashe
M
Herlyn
Meenhard
M
Smalley
Keiran S M
KS
Mahale
Alka
A
Eroshkin
Alexey
A
Aaronson
Stuart
S
Ronai
Ze'ev
Z
D001483:Base Sequence; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering
D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4