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A Ceramide-binding C1 Domain Mediates Kinase Suppressor of Ras Membrane Translocation.
- Source :
-
Cellular Physiology & Biochemistry (Karger AG) . 2009, Vol. 24 Issue 3/4, p219-230. 12p. 5 Graphs. - Publication Year :
- 2009
-
Abstract
- Genetic and biochemical data support Kinase Suppressor of Ras 1 (KSR1) as a positive regulator of the Ras-Raf-MAPK pathway, functioning as a kinase and/or scaffold to regulate c-Raf-1 activation. Membrane translocation mediated by the KSR1 CA3 domain, which is homologous to the atypical PKC C1 lipid-binding domain, is a critical step of KSR1-mediated c-Raf-1 activation. In this study, we used an ELISA to characterize the KSR1 CA3 domain as a lipid-binding moiety. Purified GST-KSR1-CA3 protein effectively binds ceramide but not other lipids including 1,2-diacylglyceol, dihydroceramide, ganglioside GM1, sphingomyelin and phosphatidylcholine. Upon epidermal growth factor stimulation of COS-7 cells, KSR1 translocates into and is activated within glycosphingolipid-enriched plasma membrane platforms. Pharmacologic inhibition of ceramide generation attenuates KSR1 translocation and KSR1 kinase activation in COS-7 cells. Disruption of two cysteines, which are indispensable for maintaining ternary structure of all C1 domains and their lipid binding capability, mitigates ceramide-binding capacity of purified GST-KSR1-CA3 protein, and inhibits full length KSR1 membrane translocation and kinase activation. These studies provide evidence for a mechanism by which the second messenger ceramide can target proteins to subcellular compartments in the process of transmembrane signal transduction. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Subjects :
- *CERAMIDES
*LIPIDS
*EPIDERMAL growth factor
*BIOLOGICAL membranes
*PROTEINS
Subjects
Details
- Language :
- English
- ISSN :
- 10158987
- Volume :
- 24
- Issue :
- 3/4
- Database :
- Academic Search Index
- Journal :
- Cellular Physiology & Biochemistry (Karger AG)
- Publication Type :
- Academic Journal
- Accession number :
- 43549390
- Full Text :
- https://doi.org/10.1159/000233248