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Vol. 24, No. 3-4, 2009
Issue release date: 2009
Section title: Original Paper
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Cell Physiol Biochem 2009;24:219–230

A Ceramide-binding C1 Domain Mediates Kinase Suppressor of Ras Membrane Translocation

Yin X.1 · Zafrullah M.1 · Lee H.1 · Haimovitz-Friedman A.2 · Fuks Z.2 · Kolesnick R.1
1Laboratory of Signal Transduction and2Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York

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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.

© 2009 S. Karger AG, Basel


Author Contacts

Richard Kolesnick MD
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, New York, NY 10021 (USA)
Tel. +1 646 888-2174, Fax: +1 646 422-0281


Article Information

Accepted: May 23, 2009
Published online: August 03, 2009
Number of Print Pages : 12


Publication Details

Cellular Physiology and Biochemistry (International Journal of Experimental Cellular Physiology, Biochemistry andPharmacology)

Vol. 24, No. 3-4, Year 2009 (Cover Date: 2009)

Journal Editor: F. Lang, Tübingen
ISSN: 1015–8987 (Print), eISSN: 1421–9778 (Online)

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: 5/23/2009
Published online: 8/3/2009
Issue release date: 2009

Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

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