Abstract 992: IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic adenocarcinoma

2020 ◽  
Author(s):  
Karol Nawalaniec ◽  
Yuxiang Wang ◽  
Romana Moench ◽  
Minghua Cao ◽  
Yueming Luo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Cell ◽  
Fibroblast Growth Factor ◽  
Pancreatic Adenocarcinoma ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Inflammatory Signaling ◽  
Human Pancreatic Adenocarcinoma

scholarly journals The Transmembrane Mutation G380R in Fibroblast Growth Factor Receptor 3 Uncouples Ligand-Mediated Receptor Activation from Down-Regulation

2000 ◽  
Vol 20 (2) ◽  
pp. 516-522 ◽  
Author(s):  
E. Monsonego-Ornan ◽  
R. Adar ◽  
T. Feferman ◽  
O. Segev ◽  
A. Yayon
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Down Regulation ◽  
Mutant Receptor ◽  
Chondrocyte Maturation ◽  
Kinetics Of

ABSTRACT A point mutation, Gly380Arg, in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leads to achondroplasia, the most common form of genetic dwarfism in humans. This substitution was suggested to enhance mutant receptor dimerization, leading to constitutive, ligand-independent activation. We found that dimerization and activation of the G380R mutant receptor are predominantly ligand dependent. However, using both transient and stable transfections, we found significant overexpression only of the mutant receptor protein. Metabolic pulse-chase experiments, cell surface labeling, and kinetics of uptake of radiolabeled ligand demonstrated a selective delay in the down-regulation of the mutant receptor. Moreover, this receptor was now resistant to ligand-mediated internalization, even at saturating ligand concentrations. Finally, transgenic mice expressing the human G380R mutant receptor under the mouse receptor transcriptional control demonstrated a markedly expanded area of FGFR3 immunoreactivity within their epiphyseal growth plates, compatible with an in vivo defect in receptor down-regulation. We propose that the achondroplasia mutation G380R uncouples ligand-mediated receptor activation from down-regulation at a site where the levels and kinetics of FGFR3 signals are crucial for chondrocyte maturation and bone formation.

scholarly journals Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3

2011 ◽  
Vol 22 (20) ◽  
pp. 3861-3873 ◽  
Author(s):  
Catherine R. Degnin ◽  
Melanie B. Laederich ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Intramembrane Proteolysis ◽  
Ligand Activation ◽  
Regulated Intramembrane Proteolysis

Fibroblast growth factor receptor 3 (FGFR3) is a major negative regulator of bone growth that inhibits the proliferation and differentiation of growth plate chondrocytes. Activating mutations of its c isoform cause dwarfism in humans; somatic mutations can drive oncogenic transformation in multiple myeloma and bladder cancer. How these distinct activities arise is not clear. FGFR3 was previously shown to undergo proteolytic cleavage in the bovine rib growth plate, but this was not explored further. Here, we show that FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3. The ectodomain is proteolytically cleaved (S1) in response to ligand-induced receptor activation, but unlike most RIP target proteins, it requires endocytosis and does not involve a metalloproteinase. S1 cleavage generates a C-terminal domain fragment that initially remains anchored in the membrane, is phosphorylated, and is spatially distinct from the intact receptor. Ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus. We identify the S1 cleavage site and show that γ-secretase mediates the S2 cleavage event. In this way we demonstrate a mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease.

scholarly journals Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction.

1996 ◽  
Vol 16 (3) ◽  
pp. 977-989 ◽  
Author(s):  
M Mohammadi ◽  
I Dikic ◽  
A Sorokin ◽  
W H Burgess ◽  
M Jaye ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Neuronal Differentiation ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Fibroblast Growth

Fibroblast growth factor receptor (FGFR) activation leads to receptor autophosphorylation and increased tyrosine phosphorylation of several intra cellular proteins. We have previously shown that autophosphorylated tyrosine 766 in FGFR1 serves as a binding site for one of the SH2 domains of phospholipase Cy and couples FGFR1 to phosphatidylinositol hydrolysis in several cell types. In this report, we describe the identification of six additional autophosphorylation sites (Y-463, Y-583, Y-585, Y-653, Y-654 and Y-730) on FGFR1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of FGFR1 and is therefore essential for FGFR1-mediated biological responses. In contrast, autophosphorylation of the remaining four tyrosines is dispensable for FGFR1-mediated mitogen-activated protein kinase activation and mitogenic signaling in L-6 cells as well as neuronal differentiation of PC12 cells. Interestingly, both the wild-type and a mutant FGFR1 (FGFR1-4F) are able to phosphorylate Shc and an unidentified Grb2-associated phosphoprotein of 90 kDa (pp90). Binding of the Grb2/Sos complex to phosphorylated Shc and pp90 may therefore be the key link between FGFR1 and the Ras signaling pathway, mito-genesis, and neuronal differentiation.

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