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Molecular and Cellular Biology, November 2006, p. 8371-8384, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.02167-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

KLHL1/MRP2 Mediates Neurite Outgrowth in a Glycogen Synthase Kinase 3ß-Dependent Manner

Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115

Received 8 November 2005/ Returned for modification 9 December 2005/ Accepted 3 September 2006

The actin-based cytoskeleton is essential for the generation and maintenance of cell polarity, cellular motility, and the formation of neural cell processes. MRP2 is an actin-binding protein of the kelch-related protein family. While MRP2 has been shown to be expressed specifically in brain, its function is still unknown. Here, we report that in neuronal growth factor (NGF)-induced PC12 cells, MRP2 was expressed along the neurite processes and colocalized with Talin at the growth cones. MRP2 mRNA and protein levels were up-regulated in PC12 cells following NGF stimulation. Moreover, treatment of PC12 cells with interfering RNAs for MRP2 and glycogen synthase kinase 3ß (GSK3ß) resulted in the inhibition of neurite outgrowth. A significant decrease in MRP2 expression levels was observed following GSK3ß inhibition, which was correlated with the inhibited neurite outgrowth, while GSK3ß overexpression was found to increase MRP2 expression levels. MRP2 interacted with GSK3ß through its NH₂ terminus containing the BTB domain, and these molecules colocalized along neurite processes and growth cones in differentiated PC12 cells and rat primary hippocampal neurons. Additionally, increased associations of MRP2 with GSK3ß and MRP2 with actin were observed in the NGF-treated PC12 cells. Thus, this study provides, for the first time, insights into the involvement of MRP2 in neurite outgrowth, which occurs in a GSK3ß-dependent manner.

Published ahead of print on 18 September 2006.

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