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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE26151 | GEO | 2011/06/30

SECONDARY ACCESSION(S): PRJNA135265

REPOSITORIES: GEO

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Project description:Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of Janus-activated kinase (JAK) / signal transducer and activator of transcription (STAT) signaling pathway. Due to complex non-linear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. To untangle these features, we used dynamic pathway modeling that employs model development and calibration based on extensive quantitative data generation. Quantitative data were collected on JAK/STAT pathway signaling components in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We showed that the amounts of STAT5 and STAT6 are higher whereas the amount of SHP1 is lower in the two lymphoma cell lines compared to B cells from healthy donors. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In our experimental setting interleukin-13 (IL13) stimulation levels remained constant over time. In MedB-1 cells surface IL13 receptor alpha 2 had a strong IL13-sequestering/decoy function. In both lymphoma cell lines we observed IL13-induced activation of interleukin-4 receptor alpha, JAK2 and STAT5, but not of STAT6, which was highly phosphorylated even without stimulus. Furthermore, the known STAT-inducible negative regulators CISH and SOCS3 were up-regulated within 2 hours in MedB-1 but not in L1236 cells. Global transcription profiling revealed 11 early and 16 sustained common genes up-regulated by IL13 in both lymphoma cell lines. Based on this detailed information we established two individual mathematical models, MedB-1 and L1236 model, which were able to describe the respective experimental data. Sensitivity analysis of the model identified six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1 cells. By inhibition of STAT5 phosphorylation we successfully validated one of the predicted targets demonstrating the potential of the approach in guiding target identification for highly deregulated signaling networks in cancer cells. We established mathematical models of the JAK/STAT pathway in two lymphoma cell types (PMBL and cHL), able to reproduce experimental data and to predict possible therapeutic targets. Cells from two lymphoma-derived cell lines, MedB-1 and L1236, were used for a time-course microarray analysis comprising stimulations with IL13 for 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h and unstimulated controls (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h), for a total of 20 microarrays per cell line.

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

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