scholarly journals Bias in FGFR1 signaling in response to FGF4, FGF8, and FGF9

2022 ◽  
Author(s):  
Kelly A Karl ◽  
Kalina Hristova ◽  
Pavel Krejci ◽  
Nuala Del Piccolo
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Cellular Responses ◽  
Ligand Recognition ◽  
Fgf Signaling ◽  
Transmembrane Helices ◽  
Downstream Signaling ◽  
Structural Differences ◽  
Mechanistic Understanding ◽  
Ligand Bias

FGFR1 signals differently in response to the FGF ligands FGF4, FGF8 and FGF9, but the mechanism behind the differential ligand recognition is poorly understood. Here, we use biophysical tools to quantify multiple aspects of FGFR1 signaling in response to the three FGFs: potency, efficacy, ligand-induced oligomerization and downregulation, and conformation of the active FGFR1 dimers. We show that FGF4, FGF8, and FGF9 are biased ligands, and that bias can explain differences in FGF8 and FGF9-mediated cellular responses. Our data suggest that ligand bias arises due to structural differences in the ligand-bound FGFR1 dimers, which impact the interactions of the FGFR1 transmembrane helices, leading to differential recruitment and activation of the downstream signaling adaptor FRS2. This study expands the mechanistic understanding of FGF signaling during development and brings the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

scholarly journals Registered report: Widespread potential for growth factor-driven resistance to anticancer kinase inhibitors

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Edward Greenfield ◽  
Erin Griner ◽  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Downstream Signaling ◽  
Rtk Inhibitors ◽  
Block Sensitivity

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from ‘Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors’ by Wilson and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The experiments that will be replicated are those reported in Figure 2B and C. In these experiments, Wilson and colleagues show that sensitivity to receptor tyrosine kinase (RTK) inhibitors can be bypassed by various ligands through reactivation of downstream signaling pathways (Figure 2A; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>), and that blocking the receptors for these bypassing ligands abrogates their ability to block sensitivity to the original RTK inhibitor (Figure 2C; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

Evidence for New Homotypic and Heterotypic Interactions between Transmembrane Helices of Proteins Involved in Receptor Tyrosine Kinase and Neuropilin Signaling

2014 ◽  
Vol 426 (24) ◽  
pp. 4099-4111 ◽  
Author(s):  
Paul Sawma ◽  
Lise Roth ◽  
Cécile Blanchard ◽  
Dominique Bagnard ◽  
Gérard Crémel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Transmembrane Helices ◽  
Heterotypic Interactions

scholarly journals Understanding RET receptor tyrosine kinase ligand recognition and chemical inhibition

2014 ◽  
Vol 70 (a1) ◽  
pp. C440-C440
Author(s):  
Emily Burns ◽  
Kerry Goodman ◽  
Svend Kjaer ◽  
Fabienne Beuron ◽  
Andrew Purkiss ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Adult Development ◽  
Receptor Tyrosine Kinase ◽  
Ligand Recognition ◽  
Chemical Inhibitors ◽  
Anti Cancer ◽  
Chemical Inhibition ◽  
Approved Drugs ◽  
Dose Dependent ◽  
Fda Approved Drugs

The RET receptor tyrosine kinase is crucial for embryonic and adult development, with mutations in both the extracellular and kinase domains leading to several types of cancer. In order to understand the mechanisms of RET activation in more detail, we have investigated how RET interacts with its bipartite ligand comprising of a glial cell line derived neurotrophic factor (GDNF) family ligand and a GDNF family receptor (GFRalpha). To visualise this interaction, we have reconstituted two vertebrate RET ternary complexes containing both ligand and co-receptor and have determined a pseudo-atomic model for a mammalian RET ternary complex using electron microscopy. Our structures reveal the basis for ligand recognition and will be presented. As RET is a validated anti-cancer target, we are actively investigating RET chemical inhibitors in collaboration with several chemistry laboratories. We have determined structures of a diverse set of chemical scaffolds bound to RET leading to an improved RET pharmacophore based on crystallographic, biochemical and cell-based data. As current FDA-approved drugs for RET-dependent metastatic thyroid cancer suffer from off-target dose-dependent toxicity and lack of specificity, we hope our data will usefully contribute to the design of second generation RET chemical inhibitors.

Specificity of FGF signaling in cell migration inDrosophila

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4563-4572 ◽  
Author(s):  
Caroline Dossenbach ◽  
Salome Röck ◽  
Markus Affolter
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Time Window ◽  
Growth Factor Receptor ◽  
Model Systems ◽  
Fgf Signaling ◽  
Fibroblast Growth Factor Receptors ◽  
Mesodermal Cell

We wanted to investigate the relationship between receptor tyrosine kinase (RTK) activated signaling pathways and the induction of cell migration. Using Drosophila tracheal and mesodermal cell migration as model systems, we find that the intracellular domain of the fibroblast growth factor receptors (FGFRs) Breathless (Btl) and Heartless (Htl) can be functionally replaced by the intracellular domains of Torso (Tor) and epidermal growth factor receptor (EGFR). These hybrid receptors can also rescue cell migration in the absence of Downstream of FGFR (Dof), a cytoplasmic protein essential for FGF signaling. These results demonstrate that tracheal and mesodermal cells respond during a specific time window to a receptor tyrosine kinase (RTK) signal with directed migration, independent of the presence or absence of Dof. We discuss our findings in the light of the recent findings that RTKs generate a generic signal that is interpreted in responding cells according to their developmental history.

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