TY - JOUR
T1 - Caveolin-1 is required for kinase suppressor of Ras 1 (KSR1)-mediated extracellular signal-regulated kinase 1/2 activation, H-RasV12-induced Senescence, and transformation
AU - Kortum, Robert L.
AU - Fernandez, Mario R.
AU - Costanzo-Garvey, Diane L.
AU - Johnson, Heidi J.
AU - Fisher, Kurt W.
AU - Volle, Deanna J.
AU - Lewis, Robert E.
PY - 2014
Y1 - 2014
N2 - The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates the activation of the Raf/MEK/extracellular signal-regulated kinase (ERK) signal transduction pathway. KSR1 disruption in mouse embryo fibroblasts (MEFs) abrogates growth factor-induced ERK activation, H-RasV12-induced replicative senescence, and H-RasV12-induced transformation. Caveolin-1 has been primarily described as a major component of the coating structure of caveolae, which can serve as a lipid binding adaptor protein and coordinates the assembly of Ras, Raf, MEK, and ERK. In this study, we show that KSR1 interacts with caveolin-1 and is responsible for MEK and ERK redistribution to caveolin-1-rich fractions. The interaction between KSR1 and caveolin-1 is essential for optimal activation of ERK as a KSR1 mutant unable to interact with caveolin-1 does not efficiently mediate growth factorinduced ERK activation at the early stages of pathway activation. Furthermore, abolishing the KSR1-caveolin-1 interaction increases growth factor demands to promote H-RasV12-induced proliferation and has adverse effects on H-RasV12-induced cellular senescence and transformation. These data show that caveolin-1 is necessary for optimal KSR1-dependent ERK activation by growth factors and oncogenic Ras.
AB - The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates the activation of the Raf/MEK/extracellular signal-regulated kinase (ERK) signal transduction pathway. KSR1 disruption in mouse embryo fibroblasts (MEFs) abrogates growth factor-induced ERK activation, H-RasV12-induced replicative senescence, and H-RasV12-induced transformation. Caveolin-1 has been primarily described as a major component of the coating structure of caveolae, which can serve as a lipid binding adaptor protein and coordinates the assembly of Ras, Raf, MEK, and ERK. In this study, we show that KSR1 interacts with caveolin-1 and is responsible for MEK and ERK redistribution to caveolin-1-rich fractions. The interaction between KSR1 and caveolin-1 is essential for optimal activation of ERK as a KSR1 mutant unable to interact with caveolin-1 does not efficiently mediate growth factorinduced ERK activation at the early stages of pathway activation. Furthermore, abolishing the KSR1-caveolin-1 interaction increases growth factor demands to promote H-RasV12-induced proliferation and has adverse effects on H-RasV12-induced cellular senescence and transformation. These data show that caveolin-1 is necessary for optimal KSR1-dependent ERK activation by growth factors and oncogenic Ras.
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U2 - 10.1128/MCB.01633-13
DO - 10.1128/MCB.01633-13
M3 - Article
C2 - 25002533
AN - SCOPUS:84906059152
SN - 0270-7306
VL - 34
SP - 3461
EP - 3472
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 18
ER -