Six years later they are …who knows where? Not a far away from the starting point (ground zero!). As I know they have focused R&D on TIE-2 and Ang1-4, and now they are talking something about new antibodies????
I guess they do not have DNA/PDLI’s expertise on antibodies/proteins modification/upgrade so that they may become therapeutic candidates.
Did Dyax validated/confirmed that TIE-1 is right and safe target? Any toxicology data (I guess we never find this?)? I am too lazy (actually busy with other staff) to listen their CCs or scientific presentations on this topic. From this two abstracts (full article available) one can speculate that TIEs/Ligands interactions may be more complex than VEGFRs/VEGFs, so exact biology of each receptor interactions with corresponding ligands is yet to be discovered????
Cheers,
Miljenko
1: J Cell Biol. 2005 Apr 25;169(2):239-43.
Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2.
Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K.
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, University of Helsinki, Finland.
The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.
PMID: 15851516 [PubMed - indexed for MEDLINE]
Mol Cell Biol. 2002 Mar;22(6):1704-13.
The endothelial receptor tyrosine kinase Tie1 activates phosphatidylinositol 3-kinase and Akt to inhibit apoptosis.
Kontos CD, Cha EH, York JD, Peters KG.
Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA. cdkontos@duke.edu
Tie1 is an orphan receptor tyrosine kinase that is expressed almost exclusively in endothelial cells and that is required for normal embryonic vascular development. Genetic studies suggest that Tie1 promotes endothelial cell survival, but other studies have suggested that the Tie1 kinase has little to no activity, and Tie1-mediated signaling pathways are unknown. To begin to study Tie1 signaling, a recombinant glutathione S-transferase (GST)-Tie1 kinase fusion protein was produced in insect cells and found to be autophosphorylated in vitro. GST-Tie1 but not a kinase-inactive mutant associated with a recombinant p85 SH2 domain protein in vitro, suggesting that Tie1 might signal through phosphatidylinositol (PI) 3-kinase. To study Tie1 signaling in a cellular context, a c-fms-Tie1 chimeric receptor (fTie1) was expressed in NIH 3T3 cells. Ligand stimulation of fTie1 resulted in Tie1 autophosphorylation and downstream activation of PI 3-kinase and Akt. Stimulation of fTie1-expressing cells potently inhibited UV irradiation-induced apoptosis in a PI 3-kinase-dependent manner. Moreover, both Akt phosphorylation and inhibition of apoptosis were abrogated by mutation of tyrosine 1113 to phenylalanine, suggesting that this residue is an important PI 3-kinase binding site. These findings are the first biochemical demonstration of a signal transduction pathway and corresponding cellular function for Tie1, and the antiapoptotic effect of Tie1 is consistent with the results of previous genetic studies.
PMID: 11865050 [PubMed - indexed for MEDLINE] |
