The p90 Ribosomal S6 Kinase (RSK) Is a Mediator of Smooth Muscle Contractility

Mykhaylo Artamonov, Ko Momotani, Darkhan Utepbergenov, Aaron Franke, Alexander Khromov, Zygmunt S. Derewenda, Avril V. Somlyo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

In the canonical model of smooth muscle (SM) contraction, the contractile force is generated by phosphorylation of the myosin regulatory light chain (RLC20) by the myosin light chain kinase (MLCK). Moreover, phosphorylation of the myosin targeting subunit (MYPT1) of the RLC20 phosphatase (MLCP) by the RhoA-dependent ROCK kinase, inhibits the phosphatase activity and consequently inhibits dephosphorylation of RLC20 with concomitant increase in contractile force, at constant intracellular [Ca2+]. This pathway is referred to as Ca2+-sensitization. There is, however, emerging evidence suggesting that additional Ser/Thr kinases may contribute to the regulatory pathways in SM. Here, we report data implicating the p90 ribosomal S6 kinase (RSK) in SM contractility. During both Ca2+- and agonist (U46619) induced SM contraction, RSK inhibition by the highly selective compound BI-D1870 (which has no effect on MLCK or ROCK) resulted in significant suppression of contractile force. Furthermore, phosphorylation levels of RLC20 and MYPT1 were both significantly decreased. Experiments involving the irreversible MLCP inhibitor microcystin-LR, in the absence of Ca2+, revealed that the decrease in phosphorylation levels of RLC20 upon RSK inhibition are not due solely to the increase in the phosphatase activity, but reflect direct or indirect phosphorylation of RLC20 by RSK. Finally, we show that agonist (U46619) stimulation of SM leads to activation of extracellular signal-regulated kinases ERK1/2 and PDK1, consistent with a canonical activation cascade for RSK. Thus, we demonstrate a novel and important physiological function of the p90 ribosomal S6 kinase, which to date has been typically associated with the regulation of gene expression.

Original languageEnglish
Article numbere58703
JournalPLoS ONE
Volume8
Issue number3
DOIs
Publication statusPublished - Mar 13 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Artamonov, M., Momotani, K., Utepbergenov, D., Franke, A., Khromov, A., Derewenda, Z. S., & Somlyo, A. V. (2013). The p90 Ribosomal S6 Kinase (RSK) Is a Mediator of Smooth Muscle Contractility. PLoS ONE, 8(3), [e58703]. https://doi.org/10.1371/journal.pone.0058703