Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-Ras^V12-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.

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ACKNOWLEDGMENTS

We thank members of the Lewis laboratory for their constructive comments. We gratefully acknowledge the assistance of Tom Dao in acquisition of images for the PLA and technical assistance by Alexander Chan. We thank Charles A. Kuszynski, Victoria Smith, and Linda M. Wilkie of the University of Nebraska Medical Center Cell Analysis Facility for their technical expertise in the generation of GFP-expressing cell lines. We thank Janice A. Taylor and James R. Talaska of the Confocal Laser Scanning Microscope Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy.

This research was supported by NIH grants R01 CA90040 and R01 DK52809 (R.E.L.). R.L.K. and K.W.F. were supported by Physician-Scientist Training Grants from the American Diabetes Association. M.R.F. was supported by the NCI Minority Supplement through NIH grant R01 CA90040, the Skala Fellowship, and training grant T32 CA09476 to the Eppley Institute for Research in Cancer and Allied Diseases. We thank the Nebraska Research Initiative and the Eppley Cancer Center for their support of the Core Facility.