title: The p90 ribosomal S6 kinase (RSK) is a mediator of smooth muscle contractility.
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 [Ca(2+)]. This pathway is referred to as Ca(2+)-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 Ca(2+)- 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 Ca(2+), 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.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Mykhaylo
authors.initials: M
authors.lastname: Artamonov
authors.forename: Ko
authors.initials: K
authors.lastname: Momotani
authors.forename: Darkhan
authors.initials: D
authors.lastname: Utepbergenov
authors.forename: Aaron
authors.initials: A
authors.lastname: Franke
authors.forename: Alexander
authors.initials: A
authors.lastname: Khromov
authors.forename: Zygmunt S
authors.initials: ZS
authors.lastname: Derewenda
authors.forename: Avril V
authors.initials: AV
authors.lastname: Somlyo
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013928:Thromboxane A2 / Q000031:analogs & derivatives
chemical_list: D007527:Isoenzymes; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012694:Serine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D011188:Potassium; D002118:Calcium