scholarly journals Critical role of the fibroblast growth factor signalling pathway in Ewing's sarcoma octamer‐binding transcription factor 4‐mediated cell proliferation and tumorigenesis

FEBS Journal ◽  
2019 ◽  
Vol 286 (22) ◽  
pp. 4443-4472 ◽  
Author(s):  
Junghoon Kim ◽  
Hyo Sun Kim ◽  
Jung‐Jae Shim ◽  
Jungwoon Lee ◽  
Ah‐young Kim ◽  
...  
2004 ◽  
Vol 24 (13) ◽  
pp. 5657-5666 ◽  
Author(s):  
Betty Lamothe ◽  
Masashi Yamada ◽  
Ute Schaeper ◽  
Walter Birchmeier ◽  
Irit Lax ◽  
...  

ABSTRACT The docking protein Gab1 has been implicated as a mediator of multiple signaling pathways that are activated by a variety of receptor tyrosine kinases and cytokines. We have previously proposed that fibroblast growth factor 1 (FGF1) stimulation of tyrosine phosphorylation of Gab1 and recruitment of phosphatidylinositol (PI) 3-kinase are mediated by an indirect mechanism in which the docking protein fibroblast receptor substrate 2α (FRS2α) plays a critical role. In this report, we explore the role of Gab1 in FGF1 signaling by using mouse embryo fibroblasts (MEFs) derived from Gab1−/− or FRS2α−/− mice. We demonstrate that Gab1 is essential for FGF1 stimulation of both PI 3-kinase and the antiapoptotic protein kinase Akt, while FGF1-induced mitogen-activated protein kinase (MAPK) stimulation is not affected by Gab1 deficiency. To test the indirect mechanism for FGF1 stimulation of PI 3-kinase and Akt, we use a chimeric docking protein composed of the membrane targeting signal and the phosphotyrosine-binding domain of FRS2α fused to the C-terminal portion of Gab1, the region including the binding sites for the complement of signaling proteins that are recruited by Gab1. We demonstrate that expression of the chimeric docking protein in Gab1−/− MEFs rescues PI 3-kinase and the Akt responses, while expression of the chimeric docking protein in FRS2α−/− MEFs rescues stimulation of both Akt and MAPK. These experiments underscore the essential role of Gab1 in FGF1 stimulation of the PI 3-kinase/Akt signaling pathway and provide further support for the indirect mechanism for FGF1 stimulation of PI 3-kinase involving regulated assembly of a multiprotein complex.


2019 ◽  
Vol 12 (1) ◽  
pp. 32-41
Author(s):  
Cristina de Miguel ◽  
Josefa Cruz ◽  
David Martín ◽  
Xavier Franch-Marro

Abstract Adult progenitor cells activation is a key event in the formation of adult organs. In Drosophila, formation of abdominal adult trachea depends on the specific activation of tracheal adult progenitors (tracheoblasts) at the Tr4 and Tr5 spiracular branches. Proliferation of these tracheoblasts generates a pool of tracheal cells that migrate toward the posterior part of the trachea by the activation of the branchless/fibroblast growth factor (Bnl/FGF) signaling to form the abdominal adult trachea. Here, we show that, in addition to migration, Bnl/FGF signaling, mediated by the transcription factor Pointed, is also required for tracheoblast proliferation. This tracheoblast activation relies on the expression of the FGF ligand bnl in their nearby branches. Finally, we show that, in the absence of the transcription factor Cut (Ct), Bnl/FGF signaling induces endoreplication of tracheoblasts partially by promoting fizzy-related expression. Altogether, our results suggest a dual role of Bnl/FGF signaling in tracheoblasts, inducing both proliferation and endoreplication, depending on the presence or absence of the transcription factor Ct, respectively.


2006 ◽  
Vol 43 (4) ◽  
pp. 327-337 ◽  
Author(s):  
Reza Forough ◽  
Brian Weylie ◽  
Charles Collins ◽  
Janet L. Parker ◽  
James Zhu ◽  
...  

2013 ◽  
Vol 450 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Makoto Shimizu ◽  
Juan Li ◽  
Ryuto Maruyama ◽  
Jun Inoue ◽  
Ryuichiro Sato

FGF19 (fibroblast growth factor 19), expressed in the small intestine, acts as an enterohepatic hormone by mediating inhibitory effects on the bile acid synthetic pathway and regulating carbohydrate and lipid metabolism. In an attempt to identify novel agents other than bile acids that induce increased FGF19 expression, we found that some ER (endoplasmic reticulum) stress inducers were effective. When intestinal epithelial Caco-2 cells were incubated with thapsigargin, marked increases were observed in the mRNA and secreted protein levels of FGF19. This was not associated with the farnesoid X receptor. Reporter gene analyses using the 5′-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays showed that ATF4 bound to this site and enhanced FGF19 expression. Overexpression of ATF4 in Caco-2 cells induced increased FGF19 mRNA expression, whereas shRNA (short hairpin RNA)-mediated depletion of ATF4 significantly attenuated a thapsigargin-induced increase in FGF19 mRNA.


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