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Development Angiopoietin - Tie2 signaling


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Development Angiopoietin - Tie2 signaling

Angiopoietin - Tie2 signaling

Angiopoietins bind exclusively to the TEK tyrosine kinase endothelial ( Tie2 )receptor tyrosine kinase. A ligand for the closely related Tyrosine kinase withimmunoglobulin-like and EGF-like domains 1 ( Tie ) receptor remains to beidentified. These ligands have opposing actions in endothelial cells as Angiopoietin1 and Angiopoietin 4 function as agonistic or activating ligands forTie2, whereas Angiopoietin 2 and Angiopoietin 3 behave as contextdependent competitive antagonists. Tie2 is highly expressed in endothelial cellsand is crucial for angiogenesis and vascular maintenance [1]. Tie isbound to Tie2 and does not signal via ligand-induced kinase activation. Thephysical association between Tie and Tie2 is consistent with Tiehaving a role in modulating Tie2 signaling [2].

The Tie2 receptor tyrosine kinase plays a pivotal role in vascular andhematopoietic development. Tie2 binds directly through SH2 domains and activatesGrowth factor receptor-bound protein 2 ( Grb2 ), Growth factor receptor-boundprotein 7 ( Grb7 ), Growth factor receptor-bound protein 14 ( Grb14 ),Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ), andPhosphoinositide-3-kinase ( PI3K ) [3]. SHP-2 and GRB2are part of the pathway upstream of mitogen-activated protein kinase ( MAPK )activation, a pathway that may be responsible for morphogenetic effects of Tie2 onendothelial cells [4].

Tie2 also binds Docking protein 2 56kDa ( DOK2 ) that recruits NCKadaptor protein 1 ( NCK1 ) and P21 protein-activated kinase 1 ( PAK1 ).This results in increased cell motility. DOK recruits RAS p21 protein activator 1( p120GAP ). This has been shown to influence cellular migration [5],[4]. DOK2 is also constitutively bound to v-crk sarcoma virus CT10oncogene homolog ( Crk ) [6].

Angiopoietin 1 via PI3K/ V-akt murine thymoma viral oncogene homolog 1(AKT(PKB)) ( AKT(PKB) )/ Forkhead box O1 ( FKHR ) initiates expression ofBaculoviral IAP repeat-containing 5 ( Survivin ), and thus protects endothelialcells from undergoing apoptosis [7], [8] and induces expressionof Angiopoietin 2 [8].

Tie2 interacts with the inhibitor of Nuclear factor kappa B ( NF-kB )activity TNFAIP3 interacting protein 2 ( ABIN-2 ) [9], [10]. ABIN-2 inhibits Receptor interacting serine-threonine kinase 1 (RIPK1 ) and Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinasegamma ( IKK-gamma ) [11]. Inhibition of NF-kB transcriptionalactivity can have anti-inflammatory and anti-apoptotic action [9], [10].

Tie2 induces Signal transducer and activators of transcription ( STAT1,STAT3 and STAT5 ) activity. Mechanisms of STAT activation remain tobe elucidated. Activated STAT induces the cell cycle inhibitor Cyclin-dependentkinase inhibitor 1A ( p21 ) expression [12].

Endothelial PAS domain protein 1 ( EPAS1 ), which forms a heterodimer with Arylhydrocarbon receptor nuclear translocator ( ARNT ), induces mRNA expression ofTie2 and a number of growth factors, leading to enhancement of mature angiogenesis[13], [14]. E74-like factor 2 ( Elf2 ) also promotesexpression of Tie2 in vascular endothelial cells in the setting of hypoxia [15].