Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis

ABSTRACT: G protein-coupled receptors (GPCRs) are well known to signal via cyclic AMP (cAMP) production at the plasma membrane, but it is now clear that various GPCRs also signal after internalization. Apart from its temporal impact through prolonging the cellular response, we wondered if the endosome-initiated signal encodes any discrete spatial information. Using the beta2-adrenoceptor (β2-AR) as a model, we show that endocytosis is required for the full repertoire of downstream cAMP-dependent transcriptional control. Next, we describe an orthogonal optogenetic approach to definitively establish that the location of cAMP production is indeed the critical variable determining the transcriptional response. Finally, our results suggest that this spatial encoding scheme helps cells functionally discriminate chemically distinct β2-AR ligands according to differences in their ability to promote receptor endocytosis. These findings reveal a discrete principle for achieving cellular signalling specificity, based on endosome-mediated spatial encoding of intracellular second messenger production and 'location aware' downstream transcriptional control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57274 | GEO | 2014/11/01

SECONDARY ACCESSION(S): PRJNA246152

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Endosomal cAMP production impacts the broad cellular phosphoproteome

Project description:Endosomal signaling from G protein-coupled receptors (GPCRs) has emerged as a novel paradigm with important pharmacological and physiological implications. Yet, our knowledge of the functional consequences of activating intracellular GPCRs is incomplete. To address this gap, we combined an optogenetic approach for site-specific generation of the prototypical second messenger cyclic AMP (cAMP) with unbiased phosphoproteomic analysis. We identified 218 unique sites that either increased or decreased in phosphorylation upon cAMP production. We next determined that the compartment of signaling origin impacted the regulation of the entire repertoire of targets in that, remarkably, endosome-derived cAMP led to more robust changes in phosphorylation for all targets regardless of their annotated sub-cellular localization. Furthermore, we observed that proteins that are dephosphorylated in response to cAMP accumulation exhibited disproportionately strong bias towards endosomal over plasma membrane signaling. Through bioinformatics analysis, we established that this specific set of targets are substrates for protein phosphatase 2A, PP2A-B56δ, and propose compartmentalized activation of PP2A as the likely underlying mechanism. Altogether, our study extends the concept that endosomal signaling is a significant functional contributor to cellular responsiveness by establishing a unique role for localized cAMP production in defining categorically distinct phosphoresponses.

2021-06-15 | PXD025775 | Pride

Wnt directs the endosomal flux of LDL-derived cholesterol and lipid droplet homeostasis

Project description:The Wnt pathway, which controls crucial steps of the development and differentiation programs, has been proposed to influence lipid storage and homeostasis. In this paper, using an unbiased strategy based on high content genome-wide RNAi screens that monitored lipid distribution and amounts, we find that Wnt3a regulates cellular cholesterol. We show that Wnt3a stimulates the production of lipid droplets, and that this stimulation strictly depends on endocytosed, LDL-derived cholesterol and on functional early and late endosomes. We also show that Wnt signaling itself controls cholesterol endocytosis and flux along the endosomal pathway, which in turn modulates cellular lipid homeostasis. These results underscore the importance of endosome functions for LD formation and reveal a previously unknown cellular program controlling lipid storage and endosome transport under the control of Wnt signaling.

2015-06-20 | E-MTAB-2872 | biostudies-arrayexpress

HEK293 femtomolar GPCR signaling

Project description:G protein-coupled receptors (GPCRs) are the largest class of cell surface signaling proteins; they participate in all physiological processes and are the targets of 30% of marketed drugs. Typically, nanomolar-micromolar concentrations of ligand are used to activate GPCRs in experimental systems. However, by measuring cAMP with increased spatial and temporal resolution, we can now detect GPCR responses to an extraordinarily wide range of ligand concentrations: from attomolar to millimolar. Mathematical modeling shows that the addition of femtomolar concentrations of ligand can activate a significant proportion of cells provided that a cell can be activated by 1-2 binding events. In addition to cAMP, activation of the endogenous b2-adrenoceptor (b2AR) and muscarinic M3R by femtomolar concentrations of ligand in cell lines and human cardiac fibroblasts causes sustained increases in nuclear ERK or cytosolic PKC, respectively. These responses are spatially and temporally distinct from those that occur at higher concentrations of ligand, and result in a unique proteomic profile. This highly sensitive signaling is dependent on the GPCRs forming pre-assembled higher-order signaling complexes at the plasma membrane. Recognizing that GPCRs respond to ultra-low concentrations of neurotransmitters and hormones challenges established paradigms of drug action and provides a new dimension of GPCR activation that is quite distinct from that typically observed.

2018-10-11 | PXD011033 | Pride

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis [siRNAGPR3]

Project description:Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of b-adrenergic G protein-coupled receptors (GPCRs). Here we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N-terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

2021-04-28 | GSE173389 | GEO

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis [hWA]

2021-04-28 | GSE173388 | GEO

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis [C-3BO]

2021-04-28 | GSE173386 | GEO

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis [hBA-OE]

2021-04-28 | GSE173404 | GEO

GPCR endocytosis confers uniformity in responses to chemically distinct ligands

Project description:This study shows that chemically and pharmacodynamically distinct agonists acting on the same GPCR can produce indistinguishable cellular responses and that this uniformity is conferred by endosomal signaling The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications but, if excessively propagated downstream, would introduce biological 'noise' compromising cognate ligand detection We asked if cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis We further demonstrate that the endosomal β2-AR signal confers uniformity on the downstream response because it is highly sensitive and saturable Based on these findings, we propose that GPCR signaling from endosomes functions as a biological noise filter to enhance reliability of cognate ligand detection

2016-11-30 | GSE87461 | GEO

Saccharomyces cerevisiae

Project description:Ras/cAMP signal transduction, perturbations

| PRJNA92621 | ENA

Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

Project description:The Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Klf5 deficient hematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect was associated with impaired bone marrow (BM) homing and lodging and decreased retention in BM. The Klf5Δ/Δ HSC/P homing defect associated with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo inducible gain-of-function of Klf5 in HSC translated into increased HSC/P adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, was decreased in Klf5Δ/Δ HSC/P. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescued the expression of activated β1/β2-integrins, adhesion and BM homing of Klf5Δ/Δ HSC/P. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/P in the BM through Rab5-dependent post-translational regulation of Beta1/Beta2 integrins. Differential gene expression analyses was performed with Affymetrix GeneChip Mouse 1.0 ST assay. LSK cells from KLF-/- (n=4) and wt (n=5), bred on a C57BL/6 background, was analyzed for differential gene expression using GeneSpring GX11 using student's T-test.

2013-01-30 | E-GEOD-43806 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data