G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Yu, Olivia M.; Brown, Joan Heller

doi:10.1124/mol.115.097857

Cited by 96 publications

(85 citation statements)

References 149 publications

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“…The Gα 12/13 proteins regulate important signaling events by the activation of the small GTPase protein RhoA, involved in the regulation of the actin cytoskeleton and cell motility (Kozasa et al, 2011; Yu and Brown, 2015). Under our experimental conditions, a significant stimulation of Gα 12/13 subunit was observed when membranes were incubated with WIN55212-2 but not with Δ 9 -THC or ACEA.…”

Section: Discussionmentioning

confidence: 99%

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

et al. 2016

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Cannabinoid receptors are able to couple to different families of G proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, Δ9-THC, WIN55212-2, and ACEA in mouse brain cortex. Stimulation of the [35S]GTPγS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13), in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 μM) was determined by scintillation proximity assay (SPA) technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.

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Section: Discussionmentioning

confidence: 99%

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

et al. 2016

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“…We have attributed the cardioprotective effect of S1P in the mouse heart following I/R to activation of S1P 2 and S1P 3 receptors [22] and more recently to activation of RhoA [25]. RhoA activation promotes actin polymerization, a response originally associated with altered contractile function but subsequently shown to also result in the accumulation of myocardin-related transcription factor A (MRTF-A) in the nucleus [34–38]. MRTF-A is a transcriptional co-activator which binds to serum response factor (SRF) to induce gene transcription [39–42].…”

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs

Castaldi

Chesini

Taylor

et al. 2016

Cellular Signalling

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Although c-kit+ cardiac progenitor cells (CPCs) are currently used in clinical trials there remain considerable gaps in our understanding of the molecular mechanisms underlying their proliferation and differentiation. G-protein coupled receptors (GPCRs) play an important role in regulating these processes in mammalian cell types thus we assessed GPCR mRNA expression in c-kit+ cells isolated from adult mouse hearts. Our data provide the first comprehensive overview of the distribution of this fundamental class of cardiac receptors in CPCs and reveals notable distinctions from that of adult cardiomyocytes. We focused on GPCRs that couple to RhoA activation in particular those for sphingosine-1 -phosphate (S1P). The S1P2 and S1P3 receptors are the most abundant S1P receptor subtypes in mouse and human CPCs while cardiomyocytes express predominantly S1P1 receptors. Treatment of CPCs with S1P, as with thrombin and serum, increased proliferation through a pathway requiring RhoA signaling, as evidenced by significant attenuation when Rho was inhibited by treatment with C3 toxin. Further analysis demonstrated that both S1P- and serum- induced proliferation are regulated through the S1P2 and S1P3 receptor subtypes which couple to Gα12/13 to elicit RhoA activation. The transcriptional co-activator MRTF-A was activated by S1P as assessed by its nuclear accumulation and induction of a RhoA/MRTF-A luciferase reporter. In addition S1P treatment increased expression of cardiac lineage markers Mef2C and GATA4 and the smooth muscle marker GATA6 through activation of MRTF-A. In conclusion, we delineate an S1P–regulated signaling pathway in CPCs that introduces the possibility of targeting S1P2/3 receptors, Gα12/13 or RhoA to influence the proliferation and commitment of c-kit+ CPCs and improve the response of the myocardium following injury.

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“…HCMV encodes four GPCRs [48] which have been modified to be used by the virus to take over the control of the host cell for its own benefit [49]. Rho GTPases which are activated through coupling of G proteins to GEFs in order to stimulate proliferation, differentiation, and inflammation in a variety of cell and types [50], are also used from HCMV for the interaction of viral components with cellular proteins. [51].…”

Section: Introductionmentioning

confidence: 99%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

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G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Cited by 96 publications

References 149 publications

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

Sphingosine 1-phosphate elicits RhoA-dependent proliferation and MRTF-A mediated gene induction in CPCs

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

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