title: 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.
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-Ras(V12)-induced replicative senescence, and H-Ras(V12)-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 factor-induced ERK activation at the early stages of pathway activation. Furthermore, abolishing the KSR1-caveolin-1 interaction increases growth factor demands to promote H-Ras(V12)-induced proliferation and has adverse effects on H-Ras(V12)-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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kortum
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Fernandez
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Costanzo-Garvey
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Johnson
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Fisher
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Deanna J
authors.initials: DJ
authors.lastname: Volle
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA rlewis@unmc.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016922:Cellular Senescence; D004622:Embryo, Mammalian / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D004815:Epidermal Growth Factor; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D018631:ras Proteins