P2Y<sub>2</sub> receptors induced cell surface redistribution of α<sub>v</sub> integrin is required for activation of ERK 1/2 in U937 cells

Chorna, Nataliya; Chevres, Migdalia; Santos‐Berríos, Cynthia; Orellano, Elsie A.; Erb, Laurie; González, Fernando

doi:10.1002/jcp.20946

Cited by 18 publications

(19 citation statements)

References 59 publications

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“…This can be explained by the ability of DCs to prime T cells in different tissues, independent of their ability to sense extracellular ATP by P2Y2 and the functional redundancy of other purinergic receptors in DC chemotaxis (19). Our results show that P2y2 deficiency led to reduced monocyte migration in response to ATP, which could be functionally linked to reduced ERK phosphorylation, an essential signaling event in cellular motility (48). Besides the migratory defect, P2y2 deficiency led to impairment of ROS production in inflammatory monocytes when stimulated with ATP.…”

Section: Discussionmentioning

confidence: 72%

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

Klämbt

Wohlfeil

Schwab

et al. 2015

The Journal of Immunology

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Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. During the initiation phase of acute GvHD, endogenous danger signals such as ATP are released and inform the innate immune system via activation of the purinergic receptor P2X7 that a noninfectious damage has occurred. A second ATP-activated purinergic receptor involved in inflammatory diseases is P2Y2. In this study, we used P2y2 2/2 mice to test the role of this receptor in GvHD. P2y2recipients experienced reduced GvHD-related mortality, IL-6 levels, enterocyte apoptosis, and histopathology scores. Chimeric mice with P2y2 deficiency restricted to hematopoietic tissues survived longer after GvHD induction than did wild-type mice. P2y2 deficiency of the recipient was connected to lower levels of myeloperoxidase in the intestinal tract of mice developing GvHD and a reduced myeloid cell signature. Selective deficiency of P2Y2 in inflammatory monocytes decreased GvHD severity. Mechanistically, P2y2 2/2 inflammatory monocytes displayed defective ERK activation and reactive oxygen species production. Compatible with a role of P2Y2 in human GvHD, the frequency of P2Y2 + cells in inflamed GvHD lesions correlated with histopathological GvHD severity. Our findings indicate a novel function for P2Y2 in ATP-activated recipient myeloid cells during GvHD, which could be exploited when targeting danger signals to prevent GvHD.

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Section: Discussionmentioning

confidence: 72%

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

Klämbt

Wohlfeil

Schwab

et al. 2015

The Journal of Immunology

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“…In addition, hCPC stimulation with UTP activated ERK1/2 (Online Figure X), a canonical inducer of cell proliferation and migration 34 that is known to crosstalk with both P2Y 2 R 35–38 and YAP signaling pathways 39–42 .…”

Section: Resultsmentioning

confidence: 99%

P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

Khalafalla

Greene

Khan

et al. 2017

Circulation Research

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Rationale Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged HF patients with genetic predispositions and/or comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impairs overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with pro-regenerative molecules ex vivo is crucial for improving the therapeutic outcome in HF patients. Objective To improve hCPC proliferation and migration responses that are critical for regeneration by targeting pro-regenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress. Methods and Results c-Kit+ hCPCs were isolated from cardiac tissue of HF patients undergoing left ventricular assist device (LVAD) implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared to fast-growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent upon activation of yes-associated protein (YAP), the downstream effector of Hippo signaling pathway. Conclusions Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling, a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in HF patients.

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“…Several tyrosine kinases, such as the proto-oncogene tyrosine-protein kinases (Src kinases) or proline-rich tyrosine kinase-2 (Pyk2), are activated by Src homology-3 (SH3)-binding sites in the C-terminal tail of P2Y2 and are involved in the transactivation of growth factor receptors (40). Src has been implicated in tumor progression because it also activates ERK1/2 and PKB pathways (41). The P2Y2 receptor can interact with integrin through an Arg-Gly-Asp motif contained in the first extracellular loop.…”

Section: Receptormentioning

confidence: 99%

Mechanisms Underlying the Opposing Effects of P2Y Receptors on the Cell Cycle

Pathak

Bhatnagar

Dubey

2008

Journal of Receptors and Signal Transduction

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The purinergic P2Y receptors are critical determinants of physiological function playing diverse roles in cell proliferation, differentiation, and survival. However, in cancer cells they have been reported to assume contradictory roles at times, thus causing inhibition of proliferation, cell death, and apoptosis. A critical evaluation and analysis of the existing experimental data show that this response is caused by multiple mechanisms at the level of the ligand, receptor, G protein, intracellular signaling, such as the mitogen activated protein kinase pathways and surface expression. This review addresses the impact of these factors in determining the outcome of P2Y receptor activation. Working in conjunction, these factors can act to produce the observed opposing effects on the cell cycle. Thus, they are important factors in the pathogenesis and control of cancer.

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P2Y₂ receptors induced cell surface redistribution of α_v integrin is required for activation of ERK 1/2 in U937 cells

Cited by 18 publications

References 59 publications

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

Mechanisms Underlying the Opposing Effects of P2Y Receptors on the Cell Cycle

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P2Y2 receptors induced cell surface redistribution of αv integrin is required for activation of ERK 1/2 in U937 cells

Cited by 18 publications

References 59 publications

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

A Novel Function for P2Y2 in Myeloid Recipient–Derived Cells during Graft-versus-Host Disease

P2Y 2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

Mechanisms Underlying the Opposing Effects of P2Y Receptors on the Cell Cycle

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P2Y₂ receptors induced cell surface redistribution of α_v integrin is required for activation of ERK 1/2 in U937 cells

P2Y ₂ Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling