UTP Transactivates Epidermal Growth Factor Receptors and Promotes Cardiomyocyte Hypertrophy Despite Inhibiting Transcription of the Hypertrophic Marker Gene, Atrial Natriuretic Peptide

Morris, James B.; Pham, Tam; Kenney, Bronywn; Sheppard, Karen E.; Woodcock, Elizabeth A.

doi:10.1074/jbc.m310012200

Cited by 30 publications

(20 citation statements)

References 32 publications

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“…The immunoblot is representative of three independent experiments. P2Y 1 R stimulates EGFR-mediated mitogenesis cells, including PC12 cells (Soltoff, 1998), MCF7 breast cancer cells (Wagstaff et al, 2000), astrocytoma cells transfected with P2Y 2 R (Liu et al, 2004), cardiomyocytes (Morris et al, 2004) and A549 lung cancer cells (Schafer et al, 2003). However, these studies analyzed neither the effects of apyrase nor the congruency between the lifetime of P2Y 2 R stimuli and proliferation requirements.…”

Section: Discussionmentioning

confidence: 96%

“…P2Y 2 R is the only other P2YR subtype previously described to mediate cell proliferation by transactivating the EGFR (Liu et al, 2004;Morris et al, 2004;Schafer et al, 2003;Soltoff et al, 1998;Wagstaff et al, 2000). P2Y 2 R is mainly activated by ATP and UTP.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y 6 R (Schafer et al, 2003) and P2Y 12 R (Van Kolen et al, 2006) are also involved in mitogenesis. To date, P2Y 2 R is the only receptor subtype to transactivate the EGFR (Liu et al, 2004;Morris et al, 2004;Schafer et al, 2003;Soltoff et al, 1998;Wagstaff et al, 2000). The short life span of extracellular nucleotides raises concern about their actual mitogenic potential, because proliferative responses can require long exposure periods to mitogenic stimuli, including EGF (Jones and Kazlauskas, 2001a;Shechter et al, 1978).…”

Section: Introductionmentioning

confidence: 99%

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Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Buvinic

Bravo‐Zehnder

Boyer

et al. 2007

Journal of Cell Science

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Epidermal growth factor receptor (EGFR) function is transregulated by a variety of stimuli, including agonists of certain G-protein-coupled receptors (GPCRs). One of the most ubiquitous GPCRs is the P2Y1 receptor (P2RY1, hereafter referred to as P2Y1R) for extracellular nucleotides, mainly ADP. Here, we show in tumoral HeLa cells and normal FRT epithelial cells that P2Y1R broadcasts mitogenic signals by transactivating the EGFR. The pathway involves PKC, Src and cell surface metalloproteases. Stimulation of P2Y1R for as little as 15-60 minutes triggers mitogenesis, mirroring the half-life of extracellular ADP. Apyrase degradation of extracellular nucleotides and drug inhibition of P2Y1R, both reduced basal cell proliferation of HeLa and FRT cells, but not MDCK cells, which do not express P2Y1R. Thus, cell-released nucleotides constitute strong mitogenic stimuli, which act via P2Y1R. Strikingly, MDCK cells ectopically expressing P2Y1R display a highly proliferative phenotype that depends on EGFR activity associated with an increased level of EGFR, thus disclosing a novel aspect of GPCR-mediated regulation of EGFR function. These results highlight a role of P2Y1R in EGFR-dependent epithelial cell proliferation. P2Y1R could potentially mediate both trophic stimuli of basally released nucleotides and first-line mitogenic stimulation upon tissue damage. It could also contribute to carcinogenesis and serve as target for antitumor therapies.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Buvinic

Bravo‐Zehnder

Boyer

et al. 2007

Journal of Cell Science

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“…Adenosine and its specific receptors were not evaluated as it did not elicit a Ca 2+ wave, induce phosphorylation of ERK or play a role in cell migration in corneal epithelial cells (Klepeis et al, 2004). In cardiomyocytes, the nucleotide UTP has been shown to transactivate EGFR (Morris et al, 2004). Still other work has shown that activation of P2Y2 receptors in PC12 cells induced EGFR in a PKC dependent manner (Soltoff 1998).…”

Section: Discussionmentioning

confidence: 99%

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

Boucher

Yang

Mayo

et al. 2007

Experimental Eye Research

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The early events that occur rapidly after injury trigger signal cascades that are essential for proper wound closure of corneal epithelial cells. We hypothesize that injury releases ATP, which stimulates purinergic receptors and elicits the phosphorylation of epidermal growth factor receptor (EGFR) tyrosine residues and subsequent cell migration by a MMP and HB-EGF dependent pathway. We demonstrated that the inhibition of purinergic receptors with the antagonist, Reactive Blue 2, abrogated the phosphorylation of EGFR and ERK. Preincubation of cells with the EGFR kinase inhibitor, AG1478, and subsequent stimulation by injury or ATP resulted in a decrease in phosphorylation of EGFR and migration. Furthermore, downregulation of EGFR by siRNA, inhibited the EGF induced intracellular Ca 2+ wave. However, the response to injury and ATP was retained indicating the presence of 2 signaling pathways. Inhibition with either CRM197 or TIMP-3 decreased injury and nucleotide induced phosphorylation of both EGFR and ERK. Incubation in the presence of a functional blocking antibody to HB-EGF also resulted in a decrease in the phosphorylation of EGFR. In addition, cell migration was inhibited by CRM197 and rescued when cells were incubated with HB-EGF. We showed that injury induced phosphorylation of specific tyrosine residues and found that a similar pattern of phosphorylation was induced by trinucleotides. These studies indicate that injury induced purinergic receptor activation leads to phosphorylation of EGFR, ERK and migration.

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“…Ang II has been shown to transactivate the EGFR in isolated cardiomyocytes 36 and whole hearts, the latter study suggesting that ADAM12 was responsible for HB-EGF shedding and subsequent cellular hypertrophy. 37 Although not necessarily the sole signaling pathway by which GPCRs stimulate cardiomyocyte hypertrophy, urotensin II, 38 endothelin-1, 37 purinergic P2Y, 39 and ␣1-adrenergic 39 receptors all stimulate cardiac enlargement via an ErbB receptordependent mechanism. Studies in renal and VSMCs further illustrate the general importance of transactivation in vascular biology.…”

Section: Transactivation Of Egf Receptors: a Common Pathway For Gpcr-mentioning

confidence: 99%

Signal Switching, Crosstalk, and Arrestin Scaffolds

Smith

Luttrell

2006

Hypertension

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H ormone agonists, including angiotensin II (Ang II), norepinephrine, urotensin II, endothelin-1, vasopressin, and serotonin, mediate a plethora of physiological and pathological cardiovascular events via their cognate 7 membrane-spanning G protein-coupled receptors (GPCRs). On ligand binding, GPCRs undergo conformational changes that enable the activation and dissociation of heterotrimeric guanine nucleotide binding proteins (G proteins) and trigger a range of intracellular second messenger signaling cascades. Because of the immediacy of second messenger generation, GPCRs are able to acutely regulate cardiovascular events such as heart rate, contractile force, and systemic vascular resistance. Compelling evidence for GPCR control in the vasculature comes from both transgenic studies and clinical findings. For example, ␤-adrenergic receptor blockers and inhibitors of the synthesis and binding of Ang II are proven antihypertensive therapeutics for humans. Furthermore, mice lacking RGS2, a regulatory protein that enhances the speed of GPCR signal termination, display marked hypertension, increased basal vascular tone, and hypersensitivity to vasoconstrictive agonists, 1 a phenotype that demonstrates the contribution of immediate GPCR-dependent signals, as well as the effect of GPCR dysregulation on cardiovascular homeostasis.The evidence that signals emanating from GPCRs also contribute to the chronic development of vascular disease is persuasive. Overexpression of the G␣q subunit in cardiomyocytes directly stimulates cardiac hypertrophy and decompensated heart failure, 2 whereas transgenic mice expressing an inhibitory fragment of G␣q exhibit reduced hypertrophy in response to pressure overload. 3 GPCR agonists like Ang II, endothelin-1, and norepinephrine, act directly on cardiomyocytes to stimulate hypertrophy. 4 Meanwhile, Ang II contributes to atherosclerosis via activation of vascular smooth muscle cell (VSMC) migration and hypertrophy; this occurs either directly, via the Ang II type 1 receptor (AT 1 R), or indirectly by stimulating endothelin-1 expression or activating inflammatory pathways. 5 Importantly, these pathological vascular effects require significant modulation of gene transcription, often via activation of growth-promoting mitogen-activated protein kinase (MAPK) cascades.A confounding issue in GPCR biology has been the incongruity between acute second messenger signals generated by ligand binding and longer-term changes in gene expression and cell growth. Indeed, studies over the past decade have demonstrated that GPCR signaling is more complicated than predicted by the ternary complex model of receptor-G protein-effector signaling. Receptor coupling specificity can be modified by phosphorylation, not only quantitatively in terms of desensitization, but also qualitatively via G protein "switching." Many, if not most, GPCRs engage in crosstalk with receptor tyrosine kinases (RTKs). Transactivation of epidermal growth factor (EGF) receptors allows GPCRs to initiate Ras-dependent signals that cont...

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UTP Transactivates Epidermal Growth Factor Receptors and Promotes Cardiomyocyte Hypertrophy Despite Inhibiting Transcription of the Hypertrophic Marker Gene, Atrial Natriuretic Peptide

Cited by 30 publications

References 32 publications

Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

Signal Switching, Crosstalk, and Arrestin Scaffolds

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