scholarly journals FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching

2020 ◽  
Vol 13 (621) ◽  
pp. eaay4353 ◽  
Author(s):  
Yongjun Yin ◽  
David M. Ornitz
Keyword(s):  
Signaling Pathways ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Signaling ◽  
Epithelial Development ◽  
Lung Epithelial ◽  
Proliferation And Differentiation ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Pseudoglandular Stage

Fibroblast growth factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelium-produced FGF9 is principally responsible for mesenchymal growth, whereas epithelium-produced FGF9 and mesenchyme-produced FGF10 guide lung epithelial development, and loss of either of these ligands affects epithelial branching. Because FGF9 and FGF10 activate distinct FGF receptors (FGFRs), we hypothesized that they would control distinct developmental processes. Here, we found that FGF9 signaled through epithelial FGFR3 to directly promote distal epithelial fate specification and inhibit epithelial differentiation. By contrast, FGF10 signaled through epithelial FGFR2b to promote epithelial proliferation and differentiation. Furthermore, FGF9-FGFR3 signaling functionally opposed FGF10-FGFR2b signaling, and FGFR3 preferentially used downstream phosphoinositide 3-kinase (PI3K) pathways, whereas FGFR2b relied on downstream mitogen-activated protein kinase (MAPK) pathways. These data demonstrate that, within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct distinct developmental functions through the activation of distinct downstream signaling pathways.

scholarly journals FGF9 and FGF10 use distinct signaling pathways to direct lung epithelial specification and branching

2019 ◽  
Author(s):  
Yongjun Yin ◽  
David M. Ornitz
Keyword(s):  
Signaling Pathways ◽  
Lung Development ◽  
Lung Epithelial Cells ◽  
Epithelial Proliferation ◽  
Fgf Receptor ◽  
Downstream Signaling ◽  
Epithelial Development ◽  
Lung Epithelial ◽  
Proliferation And Differentiation ◽  
Pseudoglandular Stage

AbstractFibroblast Growth Factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelial produced FGF9 is principally responsible for mesenchymal growth, whereas epithelial produced FGF9 and mesenchymal produced FGF10 guide lung epithelial development, and loss of either of these ligands affects epithelial branching. Because FGF9 and FGF10 activate distinct FGF receptors (FGFRs), we hypothesized that they would control distinct developmental mechanisms. Here, we show that FGF9 signaled through epithelial FGF receptor 3 (FGFR3) to directly promote distal epithelial fate specification and inhibit epithelial differentiation. By contrast, FGF10 signaled through epithelial FGFR2b to promote epithelial proliferation and differentiation. Furthermore, FGF9-FGFR3 signaling functionally opposed FGF10-FGFR2b signaling, and FGFR3 preferentially used downstream PI3K pathways, whereas FGFR2b relied on downstream RAS-MAPK pathways. These data demonstrate that within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct unique developmental functions through activation of distinct downstream signaling pathways.

scholarly journals Signaling Pathways Involved in the Regulation of mRNA Translation

2018 ◽  
Vol 38 (12) ◽  
Author(s):  
Philippe P. Roux ◽  
Ivan Topisirovic
Keyword(s):  
Signaling Pathways ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Translational Machinery ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Energy Consuming ◽  
Regulate Protein ◽  
Phosphoinositide 3 Kinase

ABSTRACTTranslation is a key step in the regulation of gene expression and one of the most energy-consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the roles of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation are among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery. While these pathways regulate protein synthesis in homeostasis, their dysregulation results in aberrant translation leading to human diseases, including diabetes, neurological disorders, and cancer. Here we review the roles of the PI3K/AKT and MAPK pathways in the regulation of mRNA translation. We also highlight additional signaling mechanisms that have recently emerged as regulators of the translational apparatus.

TNF up-regulates ST3GAL4 and sialyl-Lewisx expression in lung epithelial cells through an intronic ATF2-responsive element

2016 ◽  
Vol 474 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Florent Colomb ◽  
Marie-Ange Krzewinski-Recchi ◽  
Agata Steenackers ◽  
Audrey Vincent ◽  
Anne Harduin-Lepers ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mapk Signaling ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Sialyl Lewisx ◽  
Extracellular Signal ◽  
Potential Binding ◽  
Lung Epithelial ◽  
Mitogen Activated Protein ◽  
Responsive Element

We have previously shown that tumor necrosis factor (TNF) induced the up-regulation of the sialyltransferase gene ST3GAL4 (α2,3-sialyltransferase gene) BX transcript through mitogen- and stress-activated kinase 1/2 (MSK1/2), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. This up-regulation resulted in sialyl-Lewisx (sLex) overexpression on high-molecular-weight glycoproteins in inflamed airway epithelium and increased the adhesion of Pseudomonas aeruginosa PAO1 and PAK strains to lung epithelial cells. In the present study, we describe a TNF-responsive element in an intronic region of the ST3GAL4 gene, whose TNF-dependent activity is repressed by ERK/p38 and MSK1/2 inhibitors. This TNF-responsive element contains potential binding sites for ETS1 and ATF2 transcription factors related to TNF signaling. We also show that ATF2 is involved in TNF responsiveness, as well as in TNF-induced ST3GAL4 BX transcript and sLex overexpression in A549 lung epithelial cells. Moreover, we show that TNF induces the binding of ATF2 to the TNF-responsive element. Altogether, these data suggest that ATF2 could be a potential target to prevent inflammation-induced P. aeruginosa binding in the lung of patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis.

scholarly journals Lnk Inhibits Tpo–mpl Signaling and Tpo-mediated Megakaryocytopoiesis

2004 ◽  
Vol 200 (5) ◽  
pp. 569-580 ◽  
Author(s):  
Wei Tong ◽  
Harvey F. Lodish
Keyword(s):  
Signaling Pathways ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Pleckstrin Homology Domain ◽  
Inhibitory Function ◽  
Enhanced Sensitivity ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Thrombopoietin (Tpo) is the primary cytokine regulating megakaryocyte development and platelet production. Tpo signaling through its receptor, c-mpl, activates multiple pathways including signal transducer and activator of transcription (STAT)3, STAT5, phosphoinositide 3-kinase–Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor and immunoreceptor signaling. Here, we show that Lnk overexpression negatively regulates Tpo-mediated cell proliferation and endomitosis in hematopoietic cell lines and primary hematopoietic cells. Lnk attenuates Tpo-induced S-phase progression in 32D cells expressing mpl, and Lnk decreases Tpo-dependent megakaryocyte growth in bone marrow (BM)–derived megakaryocyte culture. Consistent with this result, we found that in both BM and spleen, Lnk-deficient mice exhibited increased numbers of megakaryocytes with increased ploidy compared with wild-type mice. In addition, Lnk-deficient megakaryocytes derived from BM and spleen showed enhanced sensitivity to Tpo during culture. The absence of Lnk caused enhanced and prolonged Tpo induction of STAT3, STAT5, Akt, and MAPK signaling pathways in CD41+ megakaryocytes. Furthermore, the Src homology 2 domain of Lnk is essential for Lnk's inhibitory function. In contrast, the conserved tyrosine near the COOH terminus is dispensable and the pleckstrin homology domain of Lnk contributes to, but is not essential for, inhibiting Tpo-dependent 32D cell growth or megakaryocyte development. Thus, Lnk negatively modulates mpl signaling pathways and is important for Tpo-mediated megakaryocytopoiesis in vivo.

Andrographolide exerted its antimicrobial effects by upregulation of human β-defensin-2 induced through p38 MAPK and NF-κB pathway in human lung epithelial cells

2012 ◽  
Vol 90 (5) ◽  
pp. 647-653 ◽  
Author(s):  
Zhen-Jun Shao ◽  
Xiao-Wei Zheng ◽  
Ting Feng ◽  
Juan Huang ◽  
Jian Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
P38 Mapk ◽  
Nuclear Factor Κb ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Antimicrobial Effects ◽  
Reverse Transcription Pcr ◽  
Lung Epithelial ◽  
Mitogen Activated Protein

Andrographis paniculata (Burm. f) Nees is a traditional herbal medicine for the treatment of infection and inflammation in China. Andrographolide (andro) is one of the major components. Human β-defensin-2 (hBD-2) is an inducible antimicrobial peptide that plays an important role in innate immunity. The present study aimed to investigate the effect of andro on upregulation of hBD-2 and the key signaling pathways involved in andro-induced hBD-2 expression. Real-time reverse transcription – PCR and Western blot assays showed that andro (1.0–10 µmol/L) can upregulate the expression of hBD-2 in a dose-dependent manner. Further studies suggested that hBD-2 mRNA and protein expression in responsive to andro were attenuated by pretreatment with SB203580 (an inhibitor of p38 mitogen-activated protein kinase (p38 MAPK)), MG-132 (an inhibitor of nuclear factor κB (NF-κB)), and an NF-κB activator inhibitor, but not by an inhibitor of ERK (PD98059) or by an inhibitor of JNK(SP600125). Moreover, we found that a second p38 MAPK inhibitor (SB202190) significantly blocked andro-mediated hBD-2 induction in SPC-A-1 lung epithelial cells. Finally, the p-c-Jun transcription factor activity assay also showed that AP-1 activity was induced by andro compared with the untreated group. We conclude that andro may exert its antimicrobial effects by upregulating the expression of hBD-2 through the p38 MAPK and NF-κB pathway.

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