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Adlung2021 - Cell-to-cell variability in JAK2/STAT5 pathway

ABSTRACT: A mathematical model for cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells

SUBMITTER: Marcel Schilling

PROVIDER: BIOMD0000001077 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000001077?filename=Adlung2021%20_model_jakstat_pa-biopax2.owl	Owl
	BIOMD0000001077?filename=Adlung2021%20_model_jakstat_pa-biopax3.owl	Owl
	BIOMD0000001077?filename=Adlung2021%20_model_jakstat_pa-matlab.m	Other
	BIOMD0000001077?filename=Adlung2021%20_model_jakstat_pa.cps	Other
	BIOMD0000001077?filename=Adlung2021%20_model_jakstat_pa.ode	Other

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Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells.

Adlung Lorenz L Stapor Paul P Tönsing Christian C Schmiester Leonard L Schwarzmüller Luisa E LE Postawa Lena L Wang Dantong D Timmer Jens J Klingmüller Ursula U Hasenauer Jan J Schilling Marcel M

Cell reports 20210801 6

Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the ...[more]

PMID: 34380040

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Bachmann2011_JAK2-STAT5_FeedbackControl

Project description:This model is from the article: Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range. Bachmann J, Raue A, Schilling M, Böhm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmüller U. Mol Syst Biol. 2011 Jul 19;7:516. 21772264 , Abstract: Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.

2024-09-02 | BIOMD0000000347 | BioModels

Splitting Function enables Dual Feedback Regulation to Control JAK2/STAT5 Signaling for a Wide Ligand Range

Project description:Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. We combined mathematical modeling and extensive time-resolved data sets in primary erythroid progenitor cells and dissected the roles of the two transcriptional feedback regulators of the SOCS family, CIS and SOCS3 in JAK2/STAT5 signaling. Our model revealed that both feedbacks are most effective at different ligand concentration ranges. To identify the relevant transcriptional feedback regulators that are involved in attenuation of Epo-induced JAK2-STAT5 signaling in addition to CIS, we performed a time-resolved genome-wide expression profiling of murine erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage up to 24 and 7 hours after EPO stimulation and in control, repectively. The analysis identified SOCS3 as the only further de novo regulated gene upon Epo-induced JAK2-STAT5 signaling. From subsequent mathematical modeling, we calculated the STAT5 response in previously unobserved Epo concentrations, which provided a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. In conclusion, our combined modeling approach revealed novel insights into the orchestrated action of feedback control to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations. Freshly sorted CFU-E cells were starved for 1 h in Panserin 401 supplemented with BSA and 50 µM β-Mercaptoethanol. Subsequently, cells were stimulated with 0.5 U/ml Epo or left untreated and RNA was extracted at different time points (0,1,2,3,4,5,6,7,8,14,19,24 hrs after Epo stimulation and at 0,1,2,3,4,5,6,7 hrs without Epo treatment) using the RNeasy Mini Plus Kit (Qiagen, Hilden, Germany).

2011-06-30 | E-GEOD-26151 | biostudies-arrayexpress

Splitting Function enables Dual Feedback Regulation to Control JAK2/STAT5 Signaling for a Wide Ligand Range

2011-06-30 | GSE26151 | GEO

Direct Targets of pSTAT5 signalling in erythropoiesis

Project description:Identification of direct transcriptional targets of EPO-JAK2-STAT5 signalling in erythroid cells

2017-09-06 | GSE94301 | GEO

Bachmann2011 - Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range

Project description:This is a dynamic pathway model examining the roles of of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK/STAT5 signaling, within the context of primary erythroid progenitor cells.

2024-09-02 | BIOMD0000000861 | BioModels

Epo-Induced Erythroid Maturation Is Dependent on PlcÎ³1 Signaling

Project description:Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells into more committed progenitors and finally into erythrocytes. Binding of erythropoietin to its receptor (EpoR) is strictly required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Jak2 tyrosine-kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (PlcÎ³1) is activated downstream of EpoR/Jak2 independently of Stat5. PlcÎ³1-deficient proerythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of PlcÎ³1 in immunophenotypically defined hematopoietic stem cells (Lin-Sca1+KIT+CD48-CD150+) severely reduced erythroid development. To identify PlcÎ³1 effector molecules involved in regulation of erythroid differentiation we assessed for changes on the level of transcription and DNA methylation after inactivation of PlcÎ³1. The single common downstream effector was H2AFY2, which encodes for the histone variant macroH2A2 (mH2A2). Suppression of macroH2A2 expression recapitulated the effects of PlcÎ³1 knockdown on erythroid maturation. Taken together, our findings identify PlcÎ³1 and its downstream target macroH2A2, as a ânon-canonicalâ signaling pathway essential for erythroid differentiation. MCIP-seq was used to interrogate methylation changes during Epo-induced differentiation of murine I/11 erythroblastic cell line upon knock-down of Plcy1 as compared to a mock control. Two different shRNA constructs that target Plcg1 were investigated at two different time points.

2015-12-31 | E-GEOD-60087 | biostudies-arrayexpress

Three distinct patterns of histone H3Y41 phosphorylation mark active genes

Project description:The aim of the project was to identify the global distribution of H3Y41ph and correlate its presence with the transcription factor STAT5 and the active histone modification H3K4me3. This was done in human erythroid leukaemia cells (HEL). HEL cells were treated with DMSO or a JAK2 inhibitor (TG101209) for 4 hours they were then crosslinked with formaldehyde and Chromatin immunoprecipitation was performed using antibodies against the proteins of interest. The DNA was then sequenced on the solexa platform. The analysis includes 7 samples: (1) H3Y41ph with DMSO, (2) H3Y41ph with TG101209, (3) STAT5 with DMSO, (4) STAT5 with TG101209, (5) IgG with DMSO, (6) H3K4me3 with DMSO, (7) independent replicate with H3Y41ph in DMSO

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Proteome in human hematopoietic stem and progenitor cell subpopulations from polycythemia vera patients and controls

Project description:Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by hyper-proliferation of the erythroid, megakaryocytic and granulocytic lineages and the presence of an activating mutation in JAK2. To elucidate mechanisms that regulate PV stem cells, we applied a newly developed data-independent acquisition (DIA) mass spectrometry (MS) technology to purified hematopoietic stem and progenitor cell (HSPC) subpopulations of patients with chronic and progressed PV. Proteomic analyses were supplemented by RNA-sequencing (RNA-seq) and identified targets validated by flow cytometry and functional in vitro assays.

2022-01-19 | PXD021178 | Pride

Calprotectin promotes anemia of inflammation in healthy and pathological conditions

Project description:Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6) that promotes the expression of the S100A8 and S100A9 genes in hematopoietic progenitors and the generation of monocytes that release CAL. The main target of CAL is an erythroid-megakaryocyte progenitor (EMP) subset. CAL prevents both erythropoietin-driven differentiation of healthy progenitors and JAK2-V617F-driven erythropoiesis. In the context of JAK2-V617F, CAL also promotes the expression of S100A8 and S100A9 genes in monocytes. The signature of CAL effects is detected in the bone marrow progenitors of patients with myeloid malignancy or severe infection. These results position CAL as a mediator of IL6 effects on triggering anemia during inflammation, an effect that is amplified in the context of JAK2-V617F-driven hematopoiesis.

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Epo-Induced Erythroid Maturation Is Dependent on Plcγ1 Signaling

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