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The Cdk5/p35 Kinases Modulate Leptin-Induced STAT3 Signaling

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Abstract

Cyclin-dependent kinase (Cdk) 5 is ubiquitously expressed in the brain and plays an essential role in central nervous system development and synaptic plasticity. The p35 kinase is a neuronal specific activator of Cdk5. Here, we show for the first time that Cdk5 activation modulates leptin signaling. P35 and its metabolite p25 were colocalized with the leptin receptor ObR in selective neurons in the hypothalamus. Overexpression of p35 alone was sufficient to induce the transcriptional activation of signal transducer and activator of transcription 3 (STAT3) in a cellular model. In retinoic acid-differentiated SH-SY5Y neuronal cells where ObRb was induced, leptin increased the expression of Cdk5, p35, and p25 kinases. The time course of induction coincided with that of phosphorylated (p)-STAT3. When Cdk5 activity was inhibited, either by roscovitine or overexpression of dominant negative Cdk5, there was a reduction of pSTAT3 activation. The results show that the activation of Cdk5 by p35 sustained leptin-induced pSTAT3 at 3–6 h. Thus, p35 is a novel modulator of leptin-induced STAT3 signaling.

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Acknowledgments

This study was supported by NIH (DK54880, NS45751, NS46528, and NS62291). The Cdk5-pcDNA3.1(–) (WT-Cdk5), dominant negative (kinase inactive) D144N Cdk5-pcDNA3.1(–) (DN-Cdk5), and p35-pEGFP-C2 plasmids originated from Prof. Yun Wang’s Laboratory (Institute of Neuroscience, Peking University, Beijing, China). The ObRb-pcDNA3.1(–) plasmid was kindly provided by Dr. Christian Bjorbaek (Harvard Medical School, Boston, MA, USA) and the pAH-Luc luciferase reporter plasmid for STAT3 activation was kindly provided by Dr. Charles Rosenblum at Merck Research Laboratories (Rahway, NJ, USA). We thank Dr. George Argyropoulos in PBRC for assistance in electroporation, Loula Burton for manuscript submission, and other members of the BBB Group for helpful discussions.

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  1. Blood–Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Yi He, Abba J. Kastin, Hung Hsuchou & Weihong Pan

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  1. Yi He
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  2. Abba J. Kastin
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Correspondence to Weihong Pan.

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He, Y., Kastin, A.J., Hsuchou, H. et al. The Cdk5/p35 Kinases Modulate Leptin-Induced STAT3 Signaling. J Mol Neurosci 39, 49–58 (2009). https://doi.org/10.1007/s12031-008-9174-3

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