Cdk5-dependent phosphorylation of p70 ribosomal S6 Kinase (S6K) is required for dendritic spine morphogenesis [Signal Transduction]

April 22nd, 2015 by Lai, K.-O., Liang, Z., Fei, E., Huang, H., Ip, N. Y.

The maturation and maintenance of dendritic spines depends on neuronal activity and protein synthesis. One potential mechanism involves mammalian target of rapamycin (mTOR), which promotes protein synthesis through phosphorylation of 4E-BP and p70 ribosomal protein S6 kinase 1 (S6K). Upon extracellular stimulation, mTOR phosphorylates S6K at Thr-389. S6K also undergoes phosphorylation at other sites, including four serine residues in the auto-inhibitory domain. Despite extensive biochemical studies, the importance of phosphorylation in the auto-inhibitory domain on S6K function remains unresolved, and its role has not been explored in the cellular context. Here we demonstrated that S6K in neuron was phosphorylated at Ser-411 within the auto-inhibitory domain by cyclin-dependent kinase 5 (Cdk5). Ser-411 phosphorylation was regulated by neuronal activity and brain-derived neurotrophic factor (BDNF). Knockdown of S6K in hippocampal neurons by RNAi led to loss of dendritic spines, an effect that mimics neuronal activity blockade by tetrodotoxin (TTX). Notably, co-expression of wild-type S6K, but not the phospho-deficient S411A mutant, could rescue the spine defects. These findings reveal the importance of Cdk5-mediated phosphorylation of S6K at Ser-411 in spine morphogenesis driven by BDNF and neuronal activity.