Phospho-PTM proteomic discovery of novel EPO- modulated kinases and phosphatases, including PTPN18 as a positive regulator of EPOR/JAK2 Signaling

Held, Matthew A.; Greenfest‐Allen, Emily; Su, Su; Stoeckert, Christian J.; Stokes, Matthew P.; Wojchowski, Don M.

doi:10.1016/j.cellsig.2020.109554

Cited by 7 publications

(7 citation statements)

References 105 publications

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“…As for the underlying mechanisms, the effects of EPO are likely mediated by EPO binding to the truncated isoform of EPOR, which has been identified in murine dopaminergic neurons [ 17 ]. Indeed, this isoform is expressed in SH-SY5Y cells, and its expression is markedly upregulated in EPO-treated cells [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

et al. 2021

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Existing therapies for Parkinson’s disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP+) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP+-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

et al. 2021

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“…RHEX protein proved to be upregulated by EPO ≥20-fold in its phosphorylation at phosphotyrosine (PY) 132 and PY141 sites, which were also implicated in binding GRB2. Beyond this, RHEX protein has been shown to comprise a likely Janus kinases-2 (JAK2) PY target and to co-immunoprecipitate with EPOR and JAK2, both of which indicate it may be involved in crosstalk between the EPOR/JAK signaling pathways ( 22 , 25 ). EPO/EPOR ligation is known to activate JAK2 kinase, JAK2 phosphorylation of EPOR cytoplasmic PY motifs, and canonical STAT, PI3K, and RAS/MEK/ERK signal transduction pathways ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of RHEX as a novel biomarker related to progression and immunity of non-small cell lung carcinoma

Xu¹,

Dai²,

Zeng³

et al. 2021

Transl Cancer Res TCR

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Background: The therapeutic response and prognosis of patients with non-small cell lung carcinoma (NSCLC) are widely related to immunity. To improve the prognosis of patients and provide reliable information to guide appropriate personalized treatment strategies, it is necessary to identify reliable prognostic or predictive indicators closely related to tumor phenotype and immune traits in NSCLC.Methods: Based on The Cancer Genome Atlas (TCGA)-NSCLC mRNA expression profile data, a novel approach combining differential gene expression analysis, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network analysis (WGCNA) was used to screen hub genes.Subsequently, the regulator of hemoglobinization and erythroid cell expansion (RHEX) was identified as a key gene using the log-rank test and confirmed in the ArrayExpress database. The relationship between RHEX and clinicopathological parameters was analyzed using the Wilcoxon rank-sum test. More importantly, through gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithms, and with reference to the Tumor IMmune Estimation Resource (TIMER) database, we explored the relevant pathways of RHEX and its relationship with tumor-infiltrating immune cells (TICs). Finally, we depicted the association between RHEX and immunomodulators in the TCGA and a web portal TISIDB. Results:The RHEX mRNA expression levels in tumor tissues were lower than those in normal tissues and declined with the progression of NSCLC. Meanwhile, RHEX overexpression was associated with high immune infiltration levels and a favorable clinical prognosis. RHEX may participate in tumor microenvironment (TME) regulation through multiple tumor-immune related pathways, especially the JAK-STAT signaling pathway. Furthermore, RHEX expression affected the infiltrating abundance of multiple TICs and positively correlated with most of the immunomodulators in NSCLC. Conclusions:Our study is the first to propose that RHEX is an immune-related gene with prognostic value in NSCLC and reveals the underlying mechanism between RHEX and tumor-immune system interactions. These results ultimately provide guidance for prognosis and immunotherapy for NSCLC patients.

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“…Another signaling molecule that associates with and modulates STAT5 activity in response to EPO is CRK-like adapter protein (CRKL) [83]. Furthermore, 22 new EPO-modified kinases and phosphatases have been recognized in a study by Held et al (2020) [84], including protein tyrosine phosphatase non-receptor type 18 (PTPN18), which is highly expressed in hematopoietic progenitors. PTPN18 has been shown not only to promote STAT5 signal transduction for EPO-dependent hematopoietic cell growth, but also signal transduction of PI3K and MAPK pathways [84].…”

Section: Regulation At the Protein Level Protein Interactions And Modifications In Stat5 Pathwaymentioning

confidence: 99%

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Tomc

Debeljak

2021

Genes

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Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

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Phospho-PTM proteomic discovery of novel EPO- modulated kinases and phosphatases, including PTPN18 as a positive regulator of EPOR/JAK2 Signaling

Cited by 7 publications

References 105 publications

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson’s Disease

Identification of RHEX as a novel biomarker related to progression and immunity of non-small cell lung carcinoma

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

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