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

Robert L. Kortum, Mario R. Fernandez, Diane L. Costanzo-Garvey, Heidi J. Johnson, Kurt W. Fisher, Deanna J. Volle, Robert E Lewis

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3461-3472
Number of pages12
JournalMolecular and cellular biology
Volume34
Issue number18
DOIs
StatePublished - Jan 1 2014

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Caveolin 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase Kinases
Cell Aging
Intercellular Signaling Peptides and Proteins
Caveolae
Fibroblast Growth Factors
KSR-1 protein kinase
Signal Transduction
Carrier Proteins
Embryonic Structures
Lipids
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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. / Kortum, Robert L.; Fernandez, Mario R.; Costanzo-Garvey, Diane L.; Johnson, Heidi J.; Fisher, Kurt W.; Volle, Deanna J.; Lewis, Robert E.

In: Molecular and cellular biology, Vol. 34, No. 18, 01.01.2014, p. 3461-3472.

Research output: Contribution to journalArticle

Kortum, Robert L. ; Fernandez, Mario R. ; Costanzo-Garvey, Diane L. ; Johnson, Heidi J. ; Fisher, Kurt W. ; Volle, Deanna J. ; Lewis, Robert E. / 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. In: Molecular and cellular biology. 2014 ; Vol. 34, No. 18. pp. 3461-3472.
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abstract = "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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