JAK/STAT: Why choose a classical or an alternative pathway when you can have both?

Puigdevall, Léna; Michiels, Camille; Stewardson, Clara; Dumoutier, Laure

doi:10.1111/jcmm.17168

Cited by 15 publications

(7 citation statements)

References 85 publications

(216 reference statements)

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“…HEK293 cells expressing V G hIFNAR1 and V C hIFNAR2Δ347, however, failed to induce STAT1 and STAT2 phosphorylation after stimulation with GCCG, CC or GC, indicating that also human IFNAR2 carry the STAT1/2 binding sites, with a major involvement of Y512 (Figure 8B). Surprisingly, Y512 which is the homologue residue to Y510 in murine IFNAR2 is not embedded in a typical STAT binding site (Puigdevall et al, 2022). We cannot, however, exclude an involvement of Y411.…”

Section: Mutational Analysis Assigned a Minor Role For Y335 And A Maj...mentioning

confidence: 73%

“…We focused on STAT1 and STAT2 phosphorylation as read-out of synthetic IFNAR activation because these are characteristic for type I IFNs. However, we are aware that overall signal transduction of type I IFNs is much more complex (Puigdevall et al, 2022). Since we did not modify the transmembrane and intracellular domain of IFNAR1 and IFNAR2 and also performed in depth transcriptomic analysis, it is, however, very likely that the replacement of the extracellular domains did not change signaling of the synthetic vs. natural receptors.…”

Section: Discussionmentioning

confidence: 99%

“…and human IFNAR2 seven intracellular tyrosine residues (269,306,316,318,337,411,512), which in both receptors might serve as STAT binding sites (Table 1), albeit the tyrosines are not imbedded in classical SH2 domain binding sites [pYxxP for STAT1, pYxxQ for STAT3, pYxxL for STAT5, pYxxF for STAT6 (Morris et al, 2018)]. However, some binding site deviations and tyrosineindependent mechanisms were described (Puigdevall et al, 2022).…”

Section: Deletion Variants For Synthetic Ifnars Assign a Major Role F...mentioning

confidence: 99%

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Synthetic mimetics assigned a major role to IFNAR2 in type I interferon signaling

Zoellner

Coesfeld²,

Vos³

et al. 2022

Front. Microbiol.

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Type I interferons (IFNs) are potent inhibitors of viral replication. Here, we reformatted the natural murine and human type I interferon-α/β receptors IFNAR1 and IFNAR2 into fully synthetic biological switches. The transmembrane and intracellular domains of natural IFNAR1 and IFNAR2 were conserved, whereas the extracellular domains were exchanged by nanobodies directed against the fluorescent proteins Green fluorescent protein (GFP) and mCherry. Using this approach, multimeric single-binding GFP-mCherry ligands induced synthetic IFNAR1/IFNAR2 receptor complexes and initiated STAT1/2 mediated signal transduction via Jak1 and Tyk2. Homodimeric GFP and mCherry ligands showed that IFNAR2 but not IFNAR1 homodimers were sufficient to induce STAT1/2 signaling. Transcriptome analysis revealed that synthetic murine type I IFN signaling was highly comparable to IFNα4 signaling. Moreover, replication of vesicular stomatitis virus (VSV) in a cell culture-based viral infection model using MC57 cells was significantly inhibited after stimulation with synthetic ligands. Using intracellular deletion variants and point mutations, Y510 and Y335 in murine IFNAR2 were verified as unique phosphorylation sites for STAT1/2 activation, whereas the other tyrosine residues in IFNAR1 and IFNAR2 were not involved in STAT1/2 phosphorylation. Comparative analysis of synthetic human IFNARs supports this finding. In summary, our data showed that synthetic type I IFN signal transduction is originating from IFNAR2 rather than IFNAR1.

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Section: Mutational Analysis Assigned a Minor Role For Y335 And A Maj...mentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Deletion Variants For Synthetic Ifnars Assign a Major Role F...mentioning

confidence: 99%

See 1 more Smart Citation

Synthetic mimetics assigned a major role to IFNAR2 in type I interferon signaling

Zoellner

Coesfeld²,

Vos³

et al. 2022

Front. Microbiol.

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“…It was observed that STAT-5A, but not STAT-5B, is critical for the cellular uptake of HNSCC. JAK2 is not essential for the stimulation of STAT-5A, but the expression of EGFR can trigger it ( Puigdevall et al, 2022 ). Consequently, STAT -5B, but not STAT-5A, is essential for the development of HNSCC in-vivo and in-vitro .…”

Section: Molecular Signaling Cascades Associated With Hnsccmentioning

confidence: 99%

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

Bhattacharjee¹,

Syeda

Rynjah³

et al. 2023

Front. Pharmacol.

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Head and neck squamous cell carcinoma is a disease that most commonly produce tumours from the lining of the epithelial cells of the lips, larynx, nasopharynx, mouth, or oro-pharynx. It is one of the most deadly forms of cancer. About one to two percent of all neo-plasm-related deaths are attributed to head and neck squamous cell carcinoma, which is responsible for about six percent of all cancers. MicroRNAs play a critical role in cell proliferation, differentiation, tumorigenesis, stress response, triggering apoptosis, and other physiological process. MicroRNAs regulate gene expression and provide new diagnostic, prognostic, and therapeutic options for head and neck squamous cell carcinoma. In this work, the role of molecular signaling pathways related to head and neck squamous cell carcinoma is emphasized. We also provide an overview of MicroRNA downregulation and overexpression and its role as a diagnostic and prognostic marker in head and neck squamous cell carcinoma. In recent years, MicroRNA nano-based therapies for head and neck squamous cell carcinoma have been explored. In addition, nanotechnology-based alternatives have been discussed as a promising strategy in exploring therapeutic paradigms aimed at improving the efficacy of conventional cytotoxic chemotherapeutic agents against head and neck squamous cell carcinoma and attenuating their cytotoxicity. This article also provides information on ongoing and recently completed clinical trials for therapies based on nanotechnology.

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“…Through this pathway, extracellular stimulations from chemical signals are transmitted to the cell nucleus to activate gene transcription. Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors are the three key components in JAK-STAT signaling (Puigdevall et al, 2022). It has been reported that various diseases, including skin conditions, immune disorders and cancers, could be the Frontiers in Pharmacology frontiersin.org consequence of dysregulated JAK-STAT signaling (Haftcheshmeh et al, 2022).…”

Section: Figurementioning

confidence: 99%

Identifying hub genes, key pathways and key immune-related genes in Peyronie’s disease by integrated bioinformatic analysis

Cui

Chen

et al. 2022

Front. Pharmacol.

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Scarring diseases, such as Peyronie’s disease (PD), usually lead to disorders in the immune system. Previous studies suggested that the PD process was regulated by immune signaling. However, the pathogenetic mechanism remains incompletely characterized. This article used bioinformatic approaches to identify hub genes, key pathways and key immune-related genes that play essential roles in PD pathogenesis. Two Gene Expression Omnibus (GEO) datasets, GSE126005 and GSE146500, were used to analyse the transcriptional profiling in both PD and normal samples. R software was applied to examine the difference in the expression of hub genes and key immune-related genes. The candidates for hub genes were further validated through protein–protein interactions (PPIs), gene correlation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. In addition, candidate miRNA‒mRNA pairs were functionally assessed. A total of 39 candidate genes were identified, the expression levels of which in PD fibroblast cells were different from those in normal cells (16 showed reduced expression in PD and 21 candidates overexpressed in PD). We found that these genes could interact with each other through PPI analysis. According to the functional enrichment analysis, the candidates may regulate some major biological processes, including cytokine‒cytokine receptor interactions and the JAK-STAT signaling pathway. IL6, IL21R, IFNE, CXCL2, EGF, and ANGPTL5 were identified as key immune-related genes. The findings may help understand the role of immunologic contributors in PD, thus shedding light on the development of more effective strategies to prevent and treat this kind of disease.

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JAK/STAT: Why choose a classical or an alternative pathway when you can have both?

Cited by 15 publications

References 85 publications

Synthetic mimetics assigned a major role to IFNAR2 in type I interferon signaling

Synthetic mimetics assigned a major role to IFNAR2 in type I interferon signaling

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

Identifying hub genes, key pathways and key immune-related genes in Peyronie’s disease by integrated bioinformatic analysis

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