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

Gang Lu, Karen A. Seta, David E. Millhorn
2005 Journal of Biological Chemistry  
Cyclin-dependent kinases (CDKs) are a family of evolutionarily conserved serine/threonine kinases. CDK2 acts as a checkpoint for the G 1 /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
more » ... ifferentiated 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.
doi:10.1074/jbc.m412498200 pmid:15824106 fatcat:bzspfm3etvdpdpdw5ltbz36uwq