Dataset Information

Bidirectional cross-regulation between ErbB2 and ?-adrenergic signalling pathways.

ABSTRACT: Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and ?2AR and ErbB2 complex in brain and heart, we hypothesized that ?-adrenergic receptors (AR) modulate ErbB2 signalling status.ErbB2 transfection of HEK293 cells up-regulates ?2AR, and ?2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2(tg)) mice have amplified response to selective ?2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with ?2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that ?2ARs levels are markedly increased in ErbB2(tg) myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with ?1- and ?2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either ?1- or ?2-AR antagonist did not completely prevent isoproterenol-induced ErbB2 expression. Furthermore, inhibition of ErbB2 kinase predisposed mice hearts to injury from chronic isoproterenol treatment while significantly reducing isoproterenol-induced pAKT and pERK levels, suggesting ErbB2's role in transactivation in the heart.Our studies show that myocardial ErbB2 and ?AR signalling are linked in a feedback loop with ?AR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating ?2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of ?-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.

SUBMITTER: Sysa-Shah P

PROVIDER: S-EPMC4752042 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways.

Sysa-Shah Polina P Tocchetti Carlo G CG Gupta Manveen M Rainer Peter P PP Shen Xiaoxu X Kang Byung-Hak BH Belmonte Frances F Li Jian J Xu Yi Y Guo Xin X Bedja Djahida D Gao Wei Dong WD Paolocci Nazareno N Rath Rutwik R Sawyer Douglas B DB Naga Prasad Sathyamangla V SV Gabrielson Kathleen K

Cardiovascular research 20151221 3

<h4>Aims</h4>Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and β2AR and ErbB2 complex in brain and heart, we hypothesized that β-adrenergic receptors (AR) modulate ErbB2 signalling status.<h4>Methods and results</h4>ErbB2 transfection of HEK293 cells up-regulates β2AR, and β2AR ...[more]

PMID: 26692570

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Project description:In cardiac myocytes, the second messenger cAMP is synthesized within the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of multiple target proteins that are functionally critical to cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase isoenzymes (PDEs). The nature of the interactions between cGMP and the PDEs, as well as between PDE isoforms, and how these ultimately transduce the cGMP signal to regulate cAMP remains unclear. To better understand this, we have developed mechanistically detailed models of PDEs 1-4, the primary cAMP-hydrolyzing PDEs in cardiac myocytes, and integrated them into a model of the β-adrenergic signaling pathway. The PDE models are based on experimental studies performed on purified PDEs which have demonstrated that cAMP and cGMP bind competitively to the cyclic nucleotide (cN)-binding domains of PDEs 1, 2, and 3, while PDE4 regulation occurs via PKA-mediated phosphorylation. Individual PDE models reproduce experimentally measured cAMP hydrolysis rates with dose-dependent cGMP regulation. The fully integrated model replicates experimentally observed whole-cell cAMP activation-response relationships and temporal dynamics upon varying degrees of β-adrenergic stimulation in cardiac myocytes. Simulations reveal that as a result of network interactions, reduction in the level of one PDE is partially compensated for by increased activation of others. PDE2 and PDE4 exert the strongest compensatory roles among all PDEs. In addition, PDE2 competes with other PDEs to bind and hydrolyze cAMP and is a strong regulator of PDE interactions. Finally, an increasing level of cGMP gradually out-competes cAMP for the catalytic sites of PDEs 1, 2, and 3, suppresses their cAMP hydrolysis rates, and results in amplified cAMP signaling. These results provide insights into how PDEs transduce cGMP signals to regulate cAMP and how PDE interactions affect cardiac β-adrenergic response.

Dataset Information

Bidirectional cross-regulation between ErbB2 and ?-adrenergic signalling pathways.

Publications

Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways.

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