title: Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy.
abstract: BACKGROUND
  Cardiac myocyte hypertrophy is the main compensatory response to chronic stress on the heart. p90 ribosomal S6 kinase (RSK) family members are effectors for extracellular signal-regulated kinases that induce myocyte growth. Although increased RSK activity has been observed in stressed myocytes, the functions of individual RSK family members have remained poorly defined, despite being potential therapeutic targets for cardiac disease.
  
  
  OBJECTIVE
  To demonstrate that type 3 RSK (RSK3) is required for cardiac myocyte hypertrophy.
  
  
  RESULTS
  RSK3 contains a unique N-terminal domain that is not conserved in other RSK family members. We show that this domain mediates the regulated binding of RSK3 to the muscle A-kinase anchoring protein scaffold, defining a novel kinase anchoring event. Disruption of both RSK3 expression using RNA interference and RSK3 anchoring using a competing muscle A-kinase anchoring protein peptide inhibited the hypertrophy of cultured myocytes. In vivo, RSK3 gene deletion in the mouse attenuated the concentric myocyte hypertrophy induced by pressure overload and catecholamine infusion.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate that anchored RSK3 transduces signals that modulate pathologic myocyte growth. Targeting of signaling complexes that contain select kinase isoforms should provide an approach for the specific inhibition of cardiac myocyte hypertrophy and for the development of novel strategies for the prevention and treatment of heart failure.
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Department of Pediatrics, University of Miami Leonard M. Miller School of Medicine, R198, P.O. Box 016960, Miami, FL 33101, USA.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kritzer
authors.forename: Jennifer J Carlisle
authors.initials: JJ
authors.lastname: Michel
authors.forename: Andrew
authors.initials: A
authors.lastname: Le
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Thakur
authors.forename: Marjorie
authors.initials: M
authors.lastname: Gayanilo
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Passariello
authors.forename: Alejandra
authors.initials: A
authors.lastname: Negro
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Danial
authors.forename: Behzad
authors.initials: B
authors.lastname: Oskouei
authors.forename: Michael
authors.initials: M
authors.lastname: Sanders
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.forename: Andre
authors.initials: A
authors.lastname: Hanauer
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dodge-Kafka
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kapiloff
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D019556:COS Cells; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C484293:Akap6 protein, rat; C507157:mAkap6 protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D007545:Isoproterenol