Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt

Fukazawa, Ryuji; Miller, Thomas A.; Kuramochi, Yukio; Frantz, Stefan; Marchionni, Mark A.; Kelly, Ralph A.; Sawyer, Douglas B.

doi:10.1016/j.yjmcc.2003.09.012

Cited by 227 publications

(195 citation statements)

References 26 publications

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“…NRG-1β binding and activation of erbB4/erbB2 receptor tyrosine kinases in myocytes induce activation of a MEK/Erk pathway, as well as a PI3-kinase/Akt pathway, leading to increased protein synthesis [10] and cell survival in the presence of cytotoxic stress [11,28], respectively. The NRG-1β/erbB2-dependent activation of Src/FAK observed here appears to be distinct from those pathways, as it was selectively suppressed by low concentrations of Src inhibitor or chronic treatment with an anti-erbB2 antibody.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which this signaling system acts to maintain cardiac structure and function remain incompletely understood. In vitro, NRG-1β induces growth and survival in cardiac myocytes via activation of MEK/Erk and PI3-kinase/Akt pathways [10,11]. However, there are also effects of NRG-1β on myocyte structure both at baseline [10] and in response to injury [7] that are not fully accounted for by these signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

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Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Kuramochi

Guo

Sawyer

2006

Journal of Molecular and Cellular Cardiology

134

100

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Cardiac myocyte erbB2 expression is required for maintenance of normal cardiac structure and function, though its role in cardiac cellular physiology is incompletely understood. We tested the hypothesis that erbB2 signaling modulates focal adhesion formation via activation of a src/FAK pathway using adult rat ventricular myocytes in primary culture. The erbB ligand neuregulin-1β (NRG-1β) induced phosphorylation of Src at Y416 and Y215, and FAK at Y861. Using antibody and pharmacological inhibitor strategies, we found that FAK activation was erbB2-and Srcdependent, but independent of PI3-kinase/Akt pathway. Furthermore, NRG-1β stimulated the formation of a multiprotein complex between erbB2, FAK, p130 CAS and paxillin within 30 min, and induced lamellipodia with longitudinal elongation of the myocytes within days. The extension of lamellipodia resulted in restoration of cell-to-cell contact between isolated myocytes, allowing for synchronous beating. These effects of NRG-1β were prevented by a src inhibitor as well as an antibody to erbB2. These results suggest the potential role of NRG-1β/erbB2/Src/FAK signaling in the maintenance and repair of electrical and mechanical coupling in cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Kuramochi

Guo

Sawyer

2006

Journal of Molecular and Cellular Cardiology

134

100

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“…To this end, we used an ErbB4 inhibitor, AG1478, which prevents ErbB4 signaling 45,46 . We found that bath-applied AG1478 prevented NRG1β-mediated suppression of the Src enhancement of synaptic NMDAR currents (Fig.…”

Section: Nrg1β-erbb4 Blocks Src Enhancement Of Nmdar Epscs In Ca1mentioning

confidence: 99%

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Pitcher

Kalia

et al. 2011

Nat Med

153

146

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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

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“…[2][3][4][5][6] Recent studies have demonstrated a critical role of topoisomerase 2b in anthracycline-induced DNA double strand breaks, which lead to mitochondrial dysfunction and formation of reactive oxygen species. 7,8 In addition, anthracyclines can disrupt intracellular calcium processing, 9 impair pro-survival signaling pathways, 10 and damage cardiac progenitor cells. 11 These pathways hinder normal myocardial growth during childhood and adolescence.…”

Section: See Related Article Pp 256-264mentioning

confidence: 99%

Anthracycline-induced cardiomyopathy: The search continues

Kim

Bergmann

2017

Journal of Nuclear Cardiology

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Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt

Cited by 227 publications

References 26 publications

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Anthracycline-induced cardiomyopathy: The search continues

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