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J. Biol. Chem., Vol. 279, Issue 27, 28592-28602, July 2, 2004

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Lipid Raft Disruption Triggers Protein Kinase C and Src-dependent Protein Kinase D Activation and Kidins220 Phosphorylation in Neuronal Cells^*

Noemí Cabrera-Poch, Lucía Sánchez-Ruiloba¶, María Rodríguez-Martínez||, and Teresa Iglesias**

From the Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), C/Arturo Duperier, 4, 28029-Madrid, Spain

Kidins220 (kinase D-interacting substrate of 220 kDa) is a novel neurospecific protein recently cloned as the first substrate for the Ser/Thr kinase protein kinase D (PKD). Herein we report that Kidins220 is constitutively associated to lipid rafts in PC12 cells, rat primary cortical neurons, and brain synaptosomes. Immunocytochemistry and confocal microscopy together with sucrose gradient fractionation show co-localization of Kidins220 and lipid raft-associated proteins. In addition, cholesterol depletion of cell membranes with methyl--cyclodextrin dramatically alters Kidins220 localization and detergent solubility. By studying the putative involvement of lipid rafts in PKD activation and signaling we have found that active PKD partitions in lipid raft fractions after sucrose gradient centrifugation and that green fluorescent protein-PKD translocates to lipid raft microdomains at the plasma membrane after phorbol ester treatment. Strikingly, lipid rafts disruption by methyl--cyclodextrin delays green fluorescent protein-PKD translocation, as determined by live cell confocal microscopy, and activates PKD, increasing Kidins220 phosphorylation on Ser⁹¹⁹ by a mechanism involving PKC and the small soluble tyrosine kinase Src. Collectively, these results reveal the importance of lipid rafts on PKD activation, translocation, and downstream signaling to its substrate Kidins220.

Received for publication, November 7, 2003 , and in revised form, April 16, 2004.

^* This work was supported by Ministerio de Ciencia y Tecnología Grant SAF2001-1703 and "Comunidad de Madrid" Grant CAM 08.5/0038/2001.1 (to T. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Supported by a postdoctoral fellowship associated with the "Comunidad de Madrid" grant CAM08.5/0038/200.1.

^¶ Recipient of an I3P fellowship supported by Invitrogen S.A. and the Consejo Superior de Investigaciones Científicas.

^|| Supported by a laboratory assistant contract associated with the "Ministerio de Ciencia y Tecnologia" grant SAF2001-1703.

^** To whom correspondence should be addressed. Tel.: 34-91-585-4487; Fax: 34-91-585-4401; E-mail: tiglesias{at}iib.uam.es.

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