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J. Biol. Chem., Vol. 282, Issue 9, 6619-6628, March 2, 2007

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Phosphorylation of Protein Phosphatase 1 by Cyclin-dependent Protein Kinase 5 during Nerve Growth Factor-induced PC12 Cell Differentiation^*

Tong Li, Lorraine E. Chalifour, and Hemant K. Paudel^¶1

From the Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital and the ^¶Department of Neurology and Neurosurgery and the Division of Experimental Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada

The transcription factor Egr-1 activates cyclin-dependent protein kinase 5 (Cdk5) during nerve growth factor (NGF)-induced differentiation of PC12 cells into neurons (Harada, T. Morooka, T., Ogawa, S., and Nishida, E. (2001) Nat. Cell Biol. 3, 453-459). The downstream target of Cdk5 in the Egr-1/Cdk5 pathway is not clear. In this study, we observed that phosphorylation of protein phosphatase 1 (PP1) on Thr³²⁰ is reduced in brain extracts from Egr-1^-/- mice, indicating that a kinase downstream of Egr-1 phosphorylates PP1. In HEK 293 cells co-transfected with PP1 and Cdk5, Cdk5 phosphorylates PP1. In vitro, Cdk5 purified from bovine brain phosphorylates bacterially expressed recombinant PP1. In NGF-treated PC12 cells, inhibition of Cdk5 by olomoucine or silencing Cdk5 expression by small interfering RNA strategy, suppresses PP1 phosphorylation. Silencing Cdk5 expression by small interfering RNA also blocks NGF-induced neurite outgrowth. Overexpression of PP1 (wild type) promotes NGF-induced differentiation of PC12 cells, whereas that of PP1 (T320A) has no effect. Our data indicate that PP1 is a downstream target of the NGF/Egr-1/Cdk5 pathway during NGF-induced differentiation of PC12 cells and suggest that PP1 phosphorylation promotes neuronal differentiation.

Received for publication, July 3, 2006 , and in revised form, December 21, 2006.

This work is dedicated to Dr. Gerald M. Carlson, professor and Chairman of the Department of Biochemistry and Molecular Biology, the University of Kansas Medical Center, Kansas City in recognition and appreciation of his mentorship.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada. Tel.: 514-340-8222, Ext. 4866; Fax: 514-340-7502; E-mail: hemant.paudel{at}mcgill.ca.

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