Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways

Kleine‐Brueggeney, Maren; Grădinaru, Irina; Babaeva, Ekaterina; Schwinn, Debra A.; Oganesian, Anush

doi:10.1016/j.cellsig.2014.05.007

Cited by 10 publications

(14 citation statements)

References 62 publications

(74 reference statements)

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“…Very few reports exist in the literature on constitutive activation of ERK1/2 by GPCRs. A naturally occurring α 1a -adrenergic receptor variant constitutively activates ERK pathway with physiological consequences 66 , 67 . Similarly, we observed constitutive ERK1/2 signaling in naturally occurring and lab-generated MC4R mutants 37 , 38 , 40 (reviewed in 39 ).…”

Section: Discussionmentioning

confidence: 99%

Biased Signaling in Naturally Occurring Mutations in Human Melanocortin-3 Receptor Gene

Yang¹,

Huang²,

Tao³

2015

Int. J. Biol. Sci.

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The melanocortin-3 receptor (MC3R) is primarily expressed in the hypothalamus and plays an important role in the regulation of energy homeostasis. Recently, some studies demonstrated that MC3R also signals through mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 signaling is known to alter gene expression, potentially contributing to the prolonged action of melanocortins on energy homeostasis regulation. In the present study, we performed detailed functional studies on 8 novel naturally occurring MC3R mutations recently reported, and the effects of endogenous MC3R agonist, α-melanocyte stimulating hormone (MSH), on ERK1/2 signaling on all 22 naturally occurring MC3R mutations reported to date. We found that mutants D158Y and L299V were potential pathogenic causes to obesity. Four residues, F82, D158, L249 and L299, played critical roles in different aspects of MC3R function. α-MSH exhibited balanced activity in Gs-cAMP and ERK1/2 signaling pathways in 15 of the 22 mutant MC3Rs. The other 7 mutant MC3Rs were biased to either one of the signaling pathways. In summary, we provided novel data about the structure-function relationship of MC3R, identifying residues important for receptor function. We also demonstrated that some mutations exhibited biased signaling, preferentially activating one intracellular signaling pathway, adding a new layer of complexity to MC3R pharmacology.

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Section: Discussionmentioning

confidence: 99%

Biased Signaling in Naturally Occurring Mutations in Human Melanocortin-3 Receptor Gene

Yang¹,

Huang²,

Tao³

2015

Int. J. Biol. Sci.

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“…Several MMPs are involved in GPCR-mediated transactivation of different RTKs such as epidermal growth factor receptor (EGFR) [ 22 , 23 , 24 , 25 ], vascular endothelial growth factor receptor (VEGFR) [ 26 , 27 , 28 ] and platelet-derived growth factor receptor (PDGFR) [ 29 , 30 ], and this process is linked to MMP-mediated shedding of ligands, which in turn activate growth factor receptors ( Figure 1 ). Several members of the MMP family are involved in the ectodomain shedding of EGFR ligands and, in turn, in EGFR transactivation.…”

Section: Ligand-dependent Triple-membrane-passing-signal (Tmps) Mementioning

confidence: 99%

“…A genetic variant of α1AR triggers a β-arrestin1/c-Src/MMP/EGFR/ERK-dependent hyperproliferation of cardiomyoblasts, which is constitutive, and Gq independent, as well as a Gq/EGFR/STAT-dependent hypertrophy, which is induced by α1AR agonists. These two distinct EGFR transactivation-dependent cascades induce the transition of cardiomyoblasts to fibroblast-like cells [ 23 ]. Urotensin II stimulation in an animal model of transverse aortic construction [ 14 ] and GPR54 stimulation by Kisspeptin-10 in human invasive breast carcinoma cells [ 110 ] represent other examples of β-arrestin-dependent EGFR transactivation.…”

Section: Role Of G Proteins and β-Arrestins In Transactivationmentioning

confidence: 99%

Cell-Surface Receptors Transactivation Mediated by G Protein-Coupled Receptors

Cattaneo

Guerra

Parisi

et al. 2014

IJMS

158

143

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G protein-coupled receptors (GPCRs) are seven transmembrane-spanning proteins belonging to a large family of cell-surface receptors involved in many intracellular signaling cascades. Despite GPCRs lack intrinsic tyrosine kinase activity, tyrosine phosphorylation of a tyrosine kinase receptor (RTK) occurs in response to binding of specific agonists of several such receptors, triggering intracellular mitogenic cascades. This suggests that the notion that GPCRs are associated with the regulation of post-mitotic cell functions is no longer believable. Crosstalk between GPCR and RTK may occur by different molecular mechanism such as the activation of metalloproteases, which can induce the metalloprotease-dependent release of RTK ligands, or in a ligand-independent manner involving membrane associated non-receptor tyrosine kinases, such as c-Src. Reactive oxygen species (ROS) are also implicated as signaling intermediates in RTKs transactivation. Intracellular concentration of ROS increases transiently in cells stimulated with GPCR agonists and their deliberated and regulated generation is mainly catalyzed by enzymes that belong to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family. Oxidation and/or reduction of cysteine sulfhydryl groups of phosphatases tightly controls the activity of RTKs and ROS-mediated inhibition of cellular phosphatases results in an equilibrium shift from the non-phosphorylated to the phosphorylated state of RTKs. Many GPCR agonists activate phospholipase C, which catalyze the hydrolysis of phosphatidylinositol 4,5-bis-phosphate to produce inositol 1,4,5-triphosphate and diacylglicerol. The consequent mobilization of Ca2+ from endoplasmic reticulum leads to the activation of protein kinase C (PKC) isoforms. PKCα mediates feedback inhibition of RTK transactivation during GPCR stimulation. Recent data have expanded the coverage of transactivation to include Serine/Threonine kinase receptors and Toll-like receptors. Herein, we discuss the main mechanisms of GPCR-mediated cell-surface receptors transactivation and the pathways involved in intracellular responses induced by GPCR agonists. These studies may suggest the design of novel strategies for therapeutic interventions.

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“…Agonist treatment of wild type receptor triggers only small, but statistically significant, EGFR-dependent cell proliferation in fibroblasts [ 29 ]. Our recent findings also reveal that EGFR transactivation by 247R triggers agonist-independent hyperproliferation and agonist-dependent hypertrophy in cardiomyoblasts [ 41 ], suggesting a common mechanism that is not cell type-dependent.…”

Section: Introductionmentioning

confidence: 78%

“…To determine whether 247R-triggered hyperproliferation in cardiovascular cells [ 29 , 41 ] is not cell type dependent but is a generalizable phenomenon, we examined proliferation of SMCs stably expressing HA-α 1a AR-247R (247R), HA-α 1a AR-WT (WT) or empty vector (control) in the presence or absence of agonists. To be close to expression levels of endogenous receptors, we purposefully used clone pairs of similar receptor densities of 247R and WT, approximately 300 fmol/mg protein, as determined by radioligand binding assays.…”

Section: Resultsmentioning

confidence: 99%

Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway

et al. 2015

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α1a Adrenergic receptors (α1aARs) are the predominant AR subtype in human vascular smooth muscle cells (SMCs). α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R) genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT) receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive) hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via β-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. β-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of β-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant), different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.

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Alpha1a-adrenoceptor genetic variant induces cardiomyoblast-to-fibroblast-like cell transition via distinct signaling pathways

Cited by 10 publications

References 62 publications

Biased Signaling in Naturally Occurring Mutations in Human Melanocortin-3 Receptor Gene

Biased Signaling in Naturally Occurring Mutations in Human Melanocortin-3 Receptor Gene

Cell-Surface Receptors Transactivation Mediated by G Protein-Coupled Receptors

Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway

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