Regulator of G-Protein Signaling 18 Controls Both Platelet Generation and Function

Delesque-Touchard, Nathalie; Pendaries, Caroline; Volle-Challier, Cécile; Millet, L; Salel, Véronique; Hervé, Caroline; Pflieger, A M; Berthou-Soulié, Laurence; Prades, Catherine; Sorg, Tania; Herbert, Jean‐Marc; Savi, Pierre; Bono, Françoise

doi:10.1371/journal.pone.0113215

Cited by 34 publications

(29 citation statements)

References 40 publications

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“…S2). These results confirmed previous reports documenting the stimulatory role of Rgs18 in megakaryocytic differentiation (Delesque-Touchard et al, 2014;Louwette et al, 2012).…”

Section: Antagonistic Functions Of Rgs18 In Erythroid and Megakaryocysupporting

confidence: 92%

“…protein overexpression). As per previous reports (Delesque-Touchard et al, 2014;Louwette et al, 2012), inhibition of Rgs18 similarly retarded megakaryocytic differentiation of fetal liver progenitors cultured in vitro ( Fig. 2) and differentiation of the murine cell line L8057 induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) (Fig.…”

Section: Antagonistic Functions Of Rgs18 In Erythroid and Megakaryocysupporting

confidence: 86%

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Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

Upadhyay¹,

Sen²

2016

Development

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Appropriate diversification of cellular lineages from multi-potent progenitors is essential for normal development and homeostasis. The specification of erythroid and megakaryocytic lineages represents an especially vital developmental event whose molecular regulation remains incompletely defined. We now demonstrate the role of Rgs18, a GTPase-activating protein and transcriptional target of the repressor Gfi1b, in regulating these processes in mouse and human cells. Gfi1b stringently represses Rgs18 expression in erythroid cells, whereas, during megakaryocytic differentiation, declining Gfi1b levels facilitate a robust induction of Rgs18. Concordantly, alterations in Rgs18 expression produce disparate outcomes by augmenting megakaryocytic and potently suppressing erythroid differentiation and vice versa. These phenotypes reflect the differential impact of Rgs18 on signaling through p38 MAPK family proteins, and ERK1 and ERK2 (also known as MAPK3 and MAPK1, respectively) in the two lineages, which in turn alter the balance between the mutually antagonistic transcription factors Fli1 and Klf1. Overall, these results identify Rgs18 as a new and crucial effector of Gfi1b that regulates downstream signaling and gene expression programs to orchestrate erythro-megakaryocytic lineage choices. This dual role of Rgs18 in reciprocally regulating divergent lineages could exemplify generic mechanisms characteristic of multiple family members in different contexts.

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“…S2). These results confirmed previous reports documenting the stimulatory role of Rgs18 in megakaryocytic differentiation (Delesque-Touchard et al, 2014;Louwette et al, 2012).…”

Section: Antagonistic Functions Of Rgs18 In Erythroid and Megakaryocysupporting

confidence: 92%

Section: Antagonistic Functions Of Rgs18 In Erythroid and Megakaryocysupporting

confidence: 86%

Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

Upadhyay¹,

Sen²

2016

Development

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“…Consistently, it was previously shown that knockdown of RGS18[24,25], RGS10[26] or mutation of the RGS binding site on Gαi[27] results in increased platelet reactivity. At this ISTH conference, Gupta et al confirmed that knockdown of RGS10 results in a gain of platelet function, in particular in response to stimulation by the second wave mediators, ADP and TxA 2 [28].…”

Section: Classical Hemostasis – Balancing Platelet Adhesiveness In CIsupporting

confidence: 77%

Platelets at the vascular interface

Bergmeier

Stefanini

2018

Research and Practice in Thrombosis and Haemostasis

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In this brief review paper, we will summarize the State-of-the-Art on how platelet reactivity is regulated in circulation and at sites of vascular injury. Our review discusses recent and ongoing work, presented at this year’s International Society on Thrombosis and Haemostasis (ISTH) meeting, on the role of platelets in (1) classical hemostasis at sites of mechanical injury, and (2) the maintenance of vascular integrity at sites of inflammation.

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“…RGS18 negatively modulates the function of G-protein-coupled receptors (GPCRs). RGS18 makes platelets less sensitive to activation (30,31). Since PLD2 can be activated downstream of GPCRs (32), it is conceivable that the increase in RGS18 is a compensatory response to some of the effects of PLD2 overexpression.…”

Section: Localization Of Wnt1-inducible Signaling Pathway Protein 1mentioning

confidence: 99%

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Chahal

Legaspi

et al. 2016

CGP

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EL4 is a murine lymphoma cell line developed in 1945 by treating C57 black mice with 9:10-dimethyl-1:2-benzanthracene (1). The cells were originally propagated in animal hosts, prior to adaptation to cell culture. EL4 cells were used for many years as a source of interleukin-2 (IL2), which they secrete when treated with phorbol 12-myristate 13-acetate (PMA).The EL4 cell line originally provided to us, by a colleague at the University of Washington, was heterogeneous with respect to PMA response. We, therefore, developed and characterized EL4 sub-lines. Wild-type (WT)-derived cell lines, which are PMA responsive, grow readily in suspension culture as did the original strain. Variant (V)-derived (PMA-resistant) sub-lines were selected for enhanced adhesion to tissue culture plastic (2). Clonal lines were developed from both cell types by limiting dilution (3). The PMA sensitivity of WT-derived cells, as reflected by PMA-induced IL2 production and mitogen-activated protein kinase (ERK1/2) activation, has been attributed to expression of Ras guanyl nucleotide releasing protein 1 (RasGRP1), which binds PMA and directly activates Ras (4); V-derived cells do not express RasGRP1.Clonal EL4 cell lines were used for experimental metastasis studies in syngeneic mice, with WT2 and V7 as prototypes (5, 6). WT2 cells do not form tumors (nonmetastatic), while V7 cells form liver tumors (metastatic) after tail vein injection. 'Metastasis' more strictly refers to tumorigenesis in this model, since circulating EL4 cells home to the liver to form tumors (5). The clonal C5 cell line was developed after stably overexpressing human hemagllutinin (HA)-tagged phospholipase D2 (PLD2) in V7 cells in order to characterize the signaling role of PLD2 using a cell line expressing little or no endogenous PLD2 (5). As compared to V7, C5 cells exhibit increased cell migration (7) and tumor growth (5), providing an early example of the positive role of PLD2 in tumorigenesis.This report presents data from microarray analyses comparing transcripts expressed by these three EL4 cell types, with the goal of further defining their phenotypes.

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Regulator of G-Protein Signaling 18 Controls Both Platelet Generation and Function

Cited by 34 publications

References 40 publications

Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

Platelets at the vascular interface

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

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