Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

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].