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J. Biol. Chem., Vol. 278, Issue 37, 35702-35709, September 12, 2003

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Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival^*

Bing-Sheng Li , Wu Ma , Howard Jaffe , Yali Zheng , Satoru Takahashi ¶, Lei Zhang ||, Ashok B. Kulkarni ¶ and Harish C. Pant  **

From the Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bethesda, Maryland 20892-4130, the Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Washington, D. C. 20375, ^¶Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, and ^||Behavioral and Endocrinology Branch, NIMH, National Institutes of Health, Bethesda, Maryland 20892

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5–/–mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.

Received for publication, February 25, 2003 , and in revised form, May 29, 2003.

^* 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.

^** To whom correspondence should be addressed: Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bldg. 36, Rm. 4D24, 9000 Rockville Pike, Bethesda, MD 20892-4130. Tel.: 301-402-2124; Fax: 301-496-1339; E-mail: panth{at}ninds.nih.gov.

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