PtdIns(3,4,5)P3, NF-KB, I-KB, 220.127.116.11, EPAS1/ARNT, TIE, Survivin, ELF2, Angiopoietin 2, TIE2, Angiopoietin 3, FKHR, p120GAP, PtdIns(4,5)P2, Grb2, RIPK1, STAT3, NCK1, Grb7, p21, DOK2, Grb14, IKK (cat), AKT(PKB), SHP-2, PI3K reg class IA, PAK1, IKK-gamma, PI3K cat class IA, Angiopoietin 1, ABIN-2, Angiopoietin 4, STAT1, STAT5, Crk
Angiopoietin - Tie2 signaling
Angiopoietins bind exclusively to the TEK tyrosine kinase endothelial ( Tie2 ) receptor tyrosine kinase. A ligand for the closely related Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 ( Tie ) receptor remains to be identified. These ligands have opposing actions in endothelial cells as Angiopoietin 1 and Angiopoietin 4 function as agonistic or activating ligands for Tie2, whereas Angiopoietin 2 and Angiopoietin 3 behave as context dependent competitive antagonists. Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance . Tie is bound to Tie2 and does not signal via ligand-induced kinase activation. The physical association between Tie and Tie2 is consistent with Tie having a role in modulating Tie2 signaling .
The Tie2 receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development. Tie2 binds directly through SH2 domains and activates Growth factor receptor-bound protein 2 ( Grb2 ), Growth factor receptor-bound protein 7 ( Grb7 ), Growth factor receptor-bound protein 14 ( Grb14 ), Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ), and Phosphoinositide-3-kinase ( PI3K ) . SHP-2 and GRB2 are part of the pathway upstream of mitogen-activated protein kinase ( MAPK ) activation, a pathway that may be responsible for morphogenetic effects of Tie2 on endothelial cells .
Tie2 also binds Docking protein 2 56kDa ( DOK2 ) that recruits NCK adaptor 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 , . DOK2 is also constitutively bound to v-crk sarcoma virus CT10 oncogene homolog ( Crk ) .
Angiopoietin 1 via PI3K/ V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) ( AKT(PKB) )/ Forkhead box O1 ( FKHR ) initiates expression of Baculoviral IAP repeat-containing 5 ( Survivin ), and thus protects endothelial cells from undergoing apoptosis ,  and induces expression of Angiopoietin 2 .
Tie2 interacts with the inhibitor of Nuclear factor kappa B ( NF-kB ) activity TNFAIP3 interacting protein 2 ( ABIN-2 ) , . ABIN-2 inhibits Receptor interacting serine-threonine kinase 1 ( RIPK1 ) and Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma ( IKK-gamma ) . Inhibition of NF-kB transcriptional activity can have anti-inflammatory and anti-apoptotic action , .
Tie2 induces Signal transducer and activators of transcription ( STAT1, STAT3 and STAT5 ) activity. Mechanisms of STAT activation remain to be elucidated. Activated STAT induces the cell cycle inhibitor Cyclin-dependent kinase inhibitor 1A ( p21 ) expression .
Endothelial PAS domain protein 1 ( EPAS1 ), which forms a heterodimer with Aryl hydrocarbon receptor nuclear translocator ( ARNT ), induces mRNA expression of Tie2 and a number of growth factors, leading to enhancement of mature angiogenesis , . E74-like factor 2 ( Elf2 ) also promotes expression of Tie2 in vascular endothelial cells in the setting of hypoxia .