scholarly journals STAT Family Protein Expression and Phosphorylation State during moDC Development Is Altered by Platinum-Based Chemotherapeutics

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Nienke de Haas ◽  
Coco de Koning ◽  
Stefania di Blasio ◽  
Georgina Flórez-Grau ◽  
I. Jolanda M. de Vries ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Platinum Drugs ◽  
Comprehensive Overview ◽  
Phosphorylation State ◽  
Stat Proteins ◽  
Gm Csf ◽  
Dc Function ◽  
Stat Signaling ◽  
Important Regulator ◽  
And Function

The STAT signaling pathway is important in dendritic cell (DC) development and function. Tumor cells can induce STAT signaling, thereby inhibiting DC maturation and immunostimulatory functions, leading to hampered efficacy of DC-based immunotherapies. Platinum-based chemotherapeutics can inhibit STAT signaling, thereby making them an interesting tool to improve DC development and function. In this study, we provide a comprehensive overview of STAT expression and phosphorylation during DC differentiation and maturation and investigate the effects of platinum drugs on STAT signaling during these processes. Monocytes were differentiated into monocyte-derived DCs (moDCs) with IL-4 and GM-CSF and matured with cytokines or TLR ligands. STAT expression and phosphorylation were analyzed by western blotting, and moDC viability and phenotype were analyzed by flow cytometry. Platinum drugs were added at day 3 of differentiation or at the start of maturation to investigate regulation of the STAT signaling pathway. All STAT proteins were expressed during moDC differentiation and STAT1, STAT5, and STAT6 were phosphorylated. No significant changes occurred in the expression and phosphorylation state of the STAT proteins during differentiation. After maturation with TLR ligands, the expression of STAT1 increased, but other STAT proteins were not affected. Phosphorylation of STAT1 and STAT3 increased during maturation, where TLR ligands induced significantly higher levels of phosphorylation than cytokines. Platinum drugs cisplatin and oxaliplatin significantly inhibited phosphorylation of STAT6 during differentiation and maturation. Treatment did not affect the phenotype or viability of the cells. As STAT6 is an important regulator of DC function, these findings suggest a role for platinum-based chemotherapeutics to enhance DC function via inhibition of STAT signaling, thereby potentially enhancing efficacy of DC-based immunotherapies.

Targeting the JAK/STAT Signaling Pathway for Breast Cancer.

2020 ◽  
Vol 28 ◽  
Author(s):  
Fei Shao ◽  
Xiaonan Pang ◽  
Gyeong Hun Baeg
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Signaling Pathway ◽  
Signal Transduction Pathway ◽  
Breast Cancer Treatment ◽  
Review Article ◽  
Transduction Pathway ◽  
Inhibitory Effects ◽  
Stat Proteins ◽  
Stat Signaling

Abstract:: Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, includ-ing radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibi-tors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

scholarly journals The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4341-4353 ◽  
Author(s):  
Pipsa Saharinen ◽  
Niklas Ekman ◽  
Krista Sarvas ◽  
Peter Parker ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Tec Family Kinase ◽  
A Tec

Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.

scholarly journals The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4341-4353 ◽  
Author(s):  
Pipsa Saharinen ◽  
Niklas Ekman ◽  
Krista Sarvas ◽  
Peter Parker ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Tec Family Kinase ◽  
A Tec

Abstract Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.

scholarly journals TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3311-3320 ◽  
Author(s):  
Michael N. Alonso ◽  
Michael T. Wong ◽  
Angela L. Zhang ◽  
Daniel Winer ◽  
Megan M. Suhoski ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Th2 Cells ◽  
Cell Contact ◽  
Th Cells ◽  
Tlr Agonists ◽  
Gm Csf ◽  
Surface Molecules ◽  
Dc Function ◽  
And Function ◽  
Inflammatory Dendritic Cells

Abstract Monocytes and T helper (TH) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that TH cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, TH1 and TH17 cells interact with monocytes and instruct these cells to differentiate into TH1- and TH17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, TH2 cells interact with monocytes and elicit the formation of TH2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas TH subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell–induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that TH-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that TH cells govern the formation and function of specialized DC subsets.

scholarly journals A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction.

1994 ◽  
Vol 14 (11) ◽  
pp. 7404-7413 ◽  
Author(s):  
S Takaki ◽  
H Kanazawa ◽  
M Shiiba ◽  
K Takatsu
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Kinase ◽  
Cytoplasmic Domain ◽  
Beta Chain ◽  
Cytoplasmic Domains ◽  
Interleukin 5 ◽  
Alpha Chain ◽  
Gm Csf ◽  
Response Expression ◽  
And Function

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils, and basophils. The IL-5 receptor (IL-5R) consists of two distinct membrane proteins, alpha and beta. The alpha chain (IL-5R alpha) is specific to IL-5. The beta chain is the common beta chain (beta c) of receptors for IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytoplasmic domains of both alpha and beta chains are essential for signal transduction. In this study, we generated cDNAs of IL-5R alpha having various mutations in their cytoplasmic domains and examined the function of these mutants by expressing them in IL-3-dependent FDC-P1 cells. The membrane-proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha, which is conserved among the alpha chains of IL-5R, IL-3R, and GM-CSF receptor (GM-CSFR), was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos, and c-myc, and tyrosine phosphorylation of cellular proteins including JAK2 protein-tyrosine kinase. In addition, analysis using chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c suggested that dimerization of the cytoplasmic domain of beta c may be an important step in activating the IL-5R complex and transducing intracellular growth signals.

scholarly journals DCBLD1 is associated with the integrin signaling pathway and has prognostic value in non-small cell lung and invasive breast carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guillaume B. Cardin ◽  
Monique Bernard ◽  
Francis Rodier ◽  
Apostolos Christopoulos
Keyword(s):  
Breast Carcinoma ◽  
Signaling Pathway ◽  
Prognostic Value ◽  
Colorectal Adenocarcinoma ◽  
Prostate Adenocarcinoma ◽  
Small Cell ◽  
Invasive Breast Carcinoma ◽  
Integrin Signaling ◽  
Small Cell Lung ◽  
And Function

AbstractGermline single nucleotide polymorphisms in the promoter region of the DCBLD1 gene are associated with non-smoking cases of both non-small cell lung carcinoma (NSCLC) and human papillomavirus-negative head and neck cancer. However the clinical relevance and function of DCBLD1 remain unclear. This multicenter retrospective study was designed to evaluate the prognostic value and function of DCBLD1 in the four main solid cancers: NSCLC, invasive breast carcinoma, colorectal adenocarcinoma and prostate adenocarcinoma. We included the following cohorts: GSE81089 NSCLC, METABRIC invasive breast carcinoma, GSE14333 colorectal adenocarcinoma, GSE70770 prostate adenocarcinoma and The Cancer Genome Atlas (TCGA) Firehose Legacy cohorts of all four cancers. DCBLD1 gene expression was associated with a worse overall survival in multivariate analyses for both NSCLC cohorts (TCGA: P = 0.03 and GSE81089: P = 0.04) and both invasive breast carcinoma cohorts (TCGA: P = 0.02 and METABRIC: P < 0.001). Patients with high DCBLD1 expression showed an upregulation of the integrin signaling pathway in comparison to those with low DCBLD1 expression in the TCGA NSCLC cohort (FDR = 5.16 × 10–14) and TCGA invasive breast carcinoma cohort (FDR = 1.94 × 10–05).

scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

Sign in / Sign up

Export Citation Format

Share Document