title: p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction.
abstract: BACKGROUND
  Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent upregulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown.
  
  
  OBJECTIVE
  We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis.
  
  
  RESULTS
  p90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac-specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI-a phenomenon fully reversible by activating ERK5.
  
  
  CONCLUSIONS
  These data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496.
authors.affiliation: University of Rochester School of Medicine and Dentistry, Aab Cardiovascular Research Institute, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Nhat-Tu
authors.initials: NT
authors.lastname: Le
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takei
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.forename: Hakjoo
authors.initials: H
authors.lastname: Lee
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Craig
authors.initials: C
authors.lastname: Morrell
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oikawa
authors.forename: Carolyn
authors.initials: C
authors.lastname: McClain
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Cathy
authors.initials: C
authors.lastname: Tournier
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Molina
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C497411:Crem protein, mouse; C497412:Crem protein, rat; D000804:Angiotensin II; D051786:Cyclic AMP Response Element Modulator; C492951:Stub1 protein, mouse; C540442:Stub1 protein, rat; D044767:Ubiquitin-Protein Ligases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5