The role of the C-terminal tail in protease-activated receptor-2-mediated Ca2+ signalling, proline-rich tyrosine kinase-2 activation, and mitogen-activated protein kinase activity

Seatter, Michael J.; Drummond, Robert M.; Kanke, Toru; Macfarlane, Scott R.; Hollenberg, Morley D.; Plevin, Robin

doi:10.1016/s0898-6568(03)00095-0

Cited by 43 publications

(42 citation statements)

References 33 publications

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“…4). Consistent with these results, a PAR2 C-tail truncation mutant lacking residues beyond serine-363 also internalized in transfected human keratinocytes (Seatter et al, 2004). One report showed that a PAR2 C-tail double point mutant, in which serine-363 and threonine-366 were converted to alanines (␦ST363/6A), was markedly defective in desensitization and internalization in KNRK cells (DeFea et al, 2000).…”

Section: Discussionsupporting

confidence: 54%

“…Activated PAR2 stimulates PI hydrolysis in multiple cell types (Bohm et al, 1996b;Seatter et al, 2004), an effect attributed to G␣ q coupling to phospholipase C-␤. Cells expressing similar amounts of PAR2 labeled with [myo-3 H]inositol were incubated in the absence or presence of trypsin for various times, and the accumulation of [ 3 H]IPs was measured.…”

Section: Resultsmentioning

confidence: 99%

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Multiple Independent Functions of Arrestins in the Regulation of Protease-Activated Receptor-2 Signaling and Trafficking

Stalheim¹,

Ding²,

Gullapalli³

et al. 2004

Mol Pharmacol

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The irreversible proteolytic nature of protease-activated receptor-2 (PAR2) activation suggests that mechanism(s) responsible for termination of receptor signaling are critical determinants of the magnitude and duration of PAR2-elicited cellular responses. Rapid desensitization of activated G-protein-coupled receptors (GPCRs) involves both phosphorylation and binding of arrestins. Arrestins also function as scaffolds and transducers of mitogen-activated protein (MAP) kinase signaling cascades. The PAR2 cytoplasmic tail (C-tail) contains multiple sites of phosphorylation and may be an important determinant for arrestin interaction. Desensitization and internalization of activated PAR2 were markedly impaired in arrestin-deficient cells compared with wild-type control cells. PAR2 C-tail truncation mutants displayed normal agonist-induced internalization, caused rapid distribution of ␤arr2-GFP to the plasma membrane, and desensitized in an arrestin-dependent manner similar to that of wild-type PAR2. It is interesting that PAR2 C-tail mutants lost the capacity to stably associate with arrestins and consequently, redistributed to endocytic vesicles without ␤arr2-GFP, whereas internalized wild-type PAR2 remained stably associated with ␤arr2-GFP in endosomes. Moreover, activated PAR2 caused rapid and prolonged activation of endogenous extracellular signal-regulated kinase (ERK1/2). It was striking that in arrestin-deficient cells, activated PAR2 induced an initial peak in ERK1/2 activity that rapidly declined. The inability of internalized PAR2 C-tail mutants to stably associate with arrestins also resulted in loss of prolonged ERK2 activation. Thus, the PAR2 C-tail regulates the stability of arrestin interaction and kinetics of ERK1/2 activation but is not essential for desensitization or internalization. These findings further suggest that the diverse functions of arrestins in regulating PAR2 signaling and trafficking are controlled by multiple independent interactions involving both the intracellular loops and the C-tail.Protease-activated receptor-2 (PAR2) is activated by multiple trypsin-like serine proteases, including trypsin, tryptase, and coagulation proteases factors VIIa and Xa, but not by thrombin (Coughlin and Camerer, 2003). Because of the irreversible proteolytic nature of PAR2 activation and the generation of a tethered ligand that cannot diffuse away, mechanisms that contribute to the termination of signaling are critical determinants of the magnitude and kinetics of protease-elicited cellular responses. The regulation of PAR1 signaling has been extensively studied (Trejo, 2003), whereas considerably less is known about PAR2. G-protein-coupled receptors (GPCRs) are initially desensitized by rapid phosphorylation of agonist-occupied receptors by GPCR serine/ threonine kinases (GRKs) and other kinases (Krupnick and Benovic, 1998). In many cases, phosphorylation enhances receptor affinity for arrestin, and arrestin binding prevents receptor-G-protein interaction, thereby uncoupling the receptor fro...

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Multiple Independent Functions of Arrestins in the Regulation of Protease-Activated Receptor-2 Signaling and Trafficking

Stalheim¹,

Ding²,

Gullapalli³

et al. 2004

Mol Pharmacol

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“…For example, PAR-2 is also expressed by endothelial cells and can regulate inflammation, 40 intracellular calcium mobilization, 41 and activation of growth factor-dependent pathways, 42 processes that take place during PH development. Similarly, in addition to tryptase, other known activators of PAR-2, such as trypsin or components of the coagulation system, could likewise contribute to the activation of this receptor in vivo and thus to the development of vascular remodeling and PH.…”

Section: Kwapiszewska Et Al Par-2 In Ph 1189mentioning

confidence: 99%

PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

Kwapiszewska

Markart

Dahal

et al. 2012

Circulation Research

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Rationale: A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH.Objective: In the present study we investigated the importance of protease-activated receptor (PAR)-2 and its ligand mast cell tryptase in the development of PH. Methods and Results:Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)-treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)-BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)-1␣ depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2-and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 ؊/؊ mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. Key Words: pulmonary arterial hypertension Ⅲ protease-activated receptor-2 Ⅲ mast cells P ulmonary hypertension (PH) is characterized by a persistent increase in pulmonary arterial pressure, which can ultimately lead to right ventricular failure and death. Factors that contribute to the increased vascular resistance in PH include vasoconstriction, vascular remodeling, and thrombosis. 1 Pulmonary vasoconstriction can result from the imbalance of vasoactive mediators such as nitric oxide, endothelin-1, prostacyclin, and serotonin. Another potent stimulator of arterial contraction is alveolar hypoxia. Low oxygen levels down-regulate voltage-gated potassium channels, leading to depolarization of smooth muscle cells (SMC), subsequent Ca 2ϩ influx, and vasoconstriction. [2][3][4] Prolonged contraction stimulates the proliferation and migration of SMC and fibroblasts leading to medial or adventitial thickening of the pulmonary arteries. 1 Remodeling can also be triggered by a dysfunction of endothelial cells, thereby altering vascular homeostasis by changing cytokine/growth factor levels and procoagulant potential. 1 Vascular damage and endothelial dysfunction can alter the composition of the extracellular matrix by the induction of matrix metalloproteinases (MMPs), resulting in SMC migration and proliferation. 5 Accumulating evidence suggests that inflammatory cells may play an active role in the development of PH. 6,7 The number of mast cells...

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“…activation by independent G-protein-and ␤-arrestin-dependent mechanisms, the former requiring Src and Ras and the latter requiring neither (1)(2)(3)12). In contrast, NK1R requires input from both G-protein-and ␤-arrestin-dependent pathways for Src and Ras-dependent activation of ERK1/2, suggesting that PAR 2 might recruit ␤-arrestins independent of G-protein coupling, whereas NK1R may rely on G-protein-mediated events for ␤-arrestin recruitment (1-3, 5, 13, 14).…”

mentioning

confidence: 99%

Divergent β-Arrestin-dependent Signaling Events Are Dependent upon Sequences within G-protein-coupled Receptor C Termini

Pal

Mathur

Kumar

et al. 2013

Journal of Biological Chemistry

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Background: Many GPCRs that utilize ␤-arrestins differ with respect to downstream signaling and cellular consequences. Results: Exchanging the C termini of two GPCRs switches the ␤-arrestin responses and relative affinities for the two receptors. Conclusion: Sequences within the C termini of different GPCRs are important for determining the nature of ␤-arrestin recruitment and signaling. Significance: These studies provide new insight regarding receptor-specific ␤-arrestin signals.

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The role of the C-terminal tail in protease-activated receptor-2-mediated Ca2+ signalling, proline-rich tyrosine kinase-2 activation, and mitogen-activated protein kinase activity

Cited by 43 publications

References 33 publications

Multiple Independent Functions of Arrestins in the Regulation of Protease-Activated Receptor-2 Signaling and Trafficking

Multiple Independent Functions of Arrestins in the Regulation of Protease-Activated Receptor-2 Signaling and Trafficking

PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

Divergent β-Arrestin-dependent Signaling Events Are Dependent upon Sequences within G-protein-coupled Receptor C Termini

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