HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 23, 21731-21738, June 10, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/23/21731    most recent M412498200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lu, G. Articles by Millhorn, D. E. Search for Related Content PubMed PubMed Citation Articles by Lu, G. Articles by Millhorn, D. E. Social Bookmarking                      What's this?

Novel Role for Cyclin-dependent Kinase 2 in Neuregulin-induced Acetylcholine Receptor Subunit Expression in Differentiated Myotubes^*

Gang Lu, Karen A. Seta, and David E. Millhorn

From the Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237

Cyclin-dependent kinases (CDKs) are a family of evolutionarily conserved serine/threonine kinases. CDK2 acts as a checkpoint for the G₁/S transition in the cell cycle. Despite a down-regulation of CDK2 activity in postmitotic cells, many cell types, including muscle cells, maintain abundant levels of CDK2 protein. This led us to hypothesize that CDK2 may have a function in postmitotic cells. We show here for the first time that CDK2 can be activated by neuregulin (NRG) in differentiated C2C12 myotubes. In addition, this activity is required for expression of the acetylcholine receptor (AChR) subunit. The switch from the fetal AChR subunit to the adult-type AChR is required for synapse maturation and the neuromuscular junction. Inhibition of CDK2 activity with either the specific CDK2 inhibitory peptide Tat-LFG or by RNA interference abolished neuregulin-induced AChR expression. Neuregulin-induced activation of CDK2 also depended on the ErbB receptor, MAPK, and PI3K, all of which have previously been shown to be required for AChR expression. Neuregulin regulated CDK2 activity through coordinating phosphorylation of CDK2 on Thr-160, accumulation of CDK2 in the nucleus, and down-regulation of the CDK2 inhibitory protein p27 in the nucleus. In addition, we also observed a novel mechanism of regulation of CDK2 activity by a low molecular weight variant of cyclin E in response to NRG. These findings establish CDK2 as an intermediate molecule that integrates NRG-activated signals from both the MAPK and PI3K pathways to AChR expression and reveal an undiscovered physiological role for CDK2 in postmitotic cells.

Received for publication, November 4, 2004 , and in revised form, March 24, 2005.

^* This work was supported by National Institutes of Health Grants HL66312, HL33831, HL59945, and DK58811. 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: Dept. of Genome Science, Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237. Tel.: 513-558-5473; Fax: 513-558-5422; E-mail: david.millhorn{at}uc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Schmetsdorf, U. Gartner, and T. Arendt Constitutive Expression of Functionally Active Cyclin-Dependent Kinases and Their Binding Partners Suggests Noncanonical Functions of Cell Cycle Regulators in Differentiated Neurons Cereb Cortex, August 1, 2007; 17(8): 1821 - 1829. [Abstract] [Full Text] [PDF]