P90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction

Nhat Tu Le, Yuichiro Takei, Tetsuro Shishido, Chang Hoon Woo, Eugene Chang, Kyungsun Heo, Hakjoo Lee, Yan Lu, Craig Morrell, Masayoshi Oikawa, Carolyn McClain, Xin Wang, Cathy Tournier, Carlos A. Molina, Jack Taunton, Chen Yan, Keigi Fujiwara, Cam Patterson, Jay Yang, Jun-ichi Abe

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

RATIONALE: 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. METHODS AND 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.

Original languageEnglish (US)
Pages (from-to)536-550
Number of pages15
JournalCirculation research
Volume110
Issue number4
DOIs
StatePublished - Feb 17 2012

Fingerprint

Ubiquitin-Protein Ligases
Apoptosis
Ligases
Ubiquitin
Myocardial Infarction
Ubiquitination
Cardiac Myocytes
Angiotensin II
Proteolysis
Up-Regulation
Heart Failure
Binding Sites
Phosphorylation

Keywords

  • MAP kinase pathway
  • apoptosis
  • diabetes mellitus
  • myocardial infarction
  • ubiquitin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

P90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. / Le, Nhat Tu; Takei, Yuichiro; Shishido, Tetsuro; Woo, Chang Hoon; Chang, Eugene; Heo, Kyungsun; Lee, Hakjoo; Lu, Yan; Morrell, Craig; Oikawa, Masayoshi; McClain, Carolyn; Wang, Xin; Tournier, Cathy; Molina, Carlos A.; Taunton, Jack; Yan, Chen; Fujiwara, Keigi; Patterson, Cam; Yang, Jay; Abe, Jun-ichi.

In: Circulation research, Vol. 110, No. 4, 17.02.2012, p. 536-550.

Research output: Contribution to journalArticle

Le, NT, Takei, Y, Shishido, T, Woo, CH, Chang, E, Heo, K, Lee, H, Lu, Y, Morrell, C, Oikawa, M, McClain, C, Wang, X, Tournier, C, Molina, CA, Taunton, J, Yan, C, Fujiwara, K, Patterson, C, Yang, J & Abe, J 2012, 'P90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction', Circulation research, vol. 110, no. 4, pp. 536-550. https://doi.org/10.1161/CIRCRESAHA.111.254730
Le, Nhat Tu ; Takei, Yuichiro ; Shishido, Tetsuro ; Woo, Chang Hoon ; Chang, Eugene ; Heo, Kyungsun ; Lee, Hakjoo ; Lu, Yan ; Morrell, Craig ; Oikawa, Masayoshi ; McClain, Carolyn ; Wang, Xin ; Tournier, Cathy ; Molina, Carlos A. ; Taunton, Jack ; Yan, Chen ; Fujiwara, Keigi ; Patterson, Cam ; Yang, Jay ; Abe, Jun-ichi. / P90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. In: Circulation research. 2012 ; Vol. 110, No. 4. pp. 536-550.
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abstract = "RATIONALE: 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. METHODS AND 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.",
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T1 - P90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction

AU - Le, Nhat Tu

AU - Takei, Yuichiro

AU - Shishido, Tetsuro

AU - Woo, Chang Hoon

AU - Chang, Eugene

AU - Heo, Kyungsun

AU - Lee, Hakjoo

AU - Lu, Yan

AU - Morrell, Craig

AU - Oikawa, Masayoshi

AU - McClain, Carolyn

AU - Wang, Xin

AU - Tournier, Cathy

AU - Molina, Carlos A.

AU - Taunton, Jack

AU - Yan, Chen

AU - Fujiwara, Keigi

AU - Patterson, Cam

AU - Yang, Jay

AU - Abe, Jun-ichi

PY - 2012/2/17

Y1 - 2012/2/17

N2 - RATIONALE: 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. METHODS AND 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.

AB - RATIONALE: 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. METHODS AND 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.

KW - MAP kinase pathway

KW - apoptosis

KW - diabetes mellitus

KW - myocardial infarction

KW - ubiquitin

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