scholarly journals Autoregulation by the Juxtamembrane Region of the Human Ephrin Receptor Tyrosine Kinase A3 (EphA3)

Structure ◽  
2008 ◽  
Vol 16 (6) ◽  
pp. 873-884 ◽  
Author(s):  
Tara L. Davis ◽  
John R. Walker ◽  
Peter Loppnau ◽  
Christine Butler-Cole ◽  
Abdellah Allali-Hassani ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Juxtamembrane Region ◽  
Ephrin Receptor

scholarly journals Targeting Ephrin Receptor Tyrosine Kinase A2 with a Selective Aptamer for Glioblastoma Stem Cells

2020 ◽  
Vol 20 ◽  
pp. 176-185 ◽  
Author(s):  
Alessandra Affinito ◽  
Cristina Quintavalle ◽  
Carla Lucia Esposito ◽  
Giuseppina Roscigno ◽  
Catello Giordano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Glioblastoma Stem Cells ◽  
Ephrin Receptor

Identification of Two Src Recruitment Sites in the Juxtamembrane Region of Flt3 with Opposing Effects on Flt3-Ligand-Induced Signaling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2289-2289
Author(s):  
Lars Ronnstrand ◽  
Elke Heiss ◽  
Christina Sundberg ◽  
Kristina Masson ◽  
Malin Pedersen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Src Family Kinases ◽  
Phosphorylation Sites ◽  
Flt3 Ligand ◽  
Erk Activation ◽  
Juxtamembrane Region ◽  
Signal Relay

Abstract Early signal relay steps upon ligand-binding to the receptor tyrosine kinase Flt3, i.e. sites of Flt3-autophosphorylation and subsequent docking partners, are mainly unresolved. Here we demonstrate for the first time identification of ligand-induced in vivo phosphorylation sites in Flt3. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region of human Flt3 and subsequent radiosequencing we identified the tyrosine residues 572, 589, 591 and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we examined Flt3-ligand-mediated responses in WT-Flt3, Y589F-Flt3 and Y599F-Flt3 expressing 32D cells. Compared to WT-Flt3-32D cells, 32D-Y589F-Flt3 showed upon ligand-stimulation enhanced Erk activation as well as proliferation/survival whereas 32D-Y599F-Flt3 cells displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for multiple signal relay molecules including Src family kinases. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed decreased FL-triggered Src activation, impaired phosphorylation of the adapter molecules Cbl and ShcA and deficient receptor ubiquitination and degradation. Interference with the Src-dependent negative regulation of Flt3 signaling may account for the enhanced mitogenic response of Y589F-Flt3. pY599 was additionally found to interact with the protein tyrosine phosphatase Shp2. As Y599F-Flt3-32D lacked ligand-induced Shp2 phosphorylation and since silencing of Shp2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3-phenotype we hypothesize that recruitment of Shp2 to pY599 contributes to FL-mediated Erk activation and proliferation. To summarize, our work presents novel insights in Flt3-mediated signal transduction. We have identified the in vivo autophosphorylation sites of the juxtamembrane region of Flt3, revealed Src family kinases and Shp2 as binding partners of pY589 and/or pY599, respectively, as well as their potential impact on FL-mediated signaling in Flt3-32D cells. Future work will now focus on elucidation of additional and possibly novel interaction partners of the found phosphorylation sites by employing an unbiased proteomics approach. With this gained knowledge it will be of interest to see whether ITDs differing in the nature of the duplicated tyrosines also confer distinct signaling behavior. If so, these tyrosines might serve as a diagnostic marker and point towards a successful combinatorial therapy consisting of a receptor tyrosine kinase inhibitor and an inhibitor for the specifically affected signal transduction pathway.

scholarly journals Radiopharmacologist’s and Radiochemist’s View on Targeting the Eph/Ephrin Receptor Tyrosine Kinase System

ACS Omega ◽  
2020 ◽  
Vol 5 (27) ◽  
pp. 16318-16331 ◽  
Author(s):  
Christin Neuber ◽  
Birgit Belter ◽  
Constantin Mamat ◽  
Jens Pietzsch
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Ephrin Receptor
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