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 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 can behave as context dependent competitive antagonists [1]. But as well Angiopoietin 2 was shown to be a partial agonist of Tie2 and induces its internalization [2]. Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance [1]. 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 [3].

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) [4]. 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 [5].

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 [5], [6]. DOK2 is also constitutively bound to v-crk sarcoma virus CT10 oncogene homolog (Crk) [7].

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 [8], [9] and induces expression of Angiopoietin 2 [9].

Tie2 interacts with the inhibitor of Nuclear factor kappa B (NF-kB) activity TNFAIP3 interacting protein 2 (ABIN-2) [10], [11]. 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) [12]. Inhibition of NF-kB transcriptional activity can have anti-inflammatory and anti-apoptotic action [10], [11].

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 [13].

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 [14], [15]. E74-like factor 2 (Elf2) also promotes expression of Tie2 in vascular endothelial cells in the setting of hypoxia [16].

References:

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   Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nature reviews. Molecular cell biology 2001 Apr;2(4):257-67
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   Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. Journal of cell science 2006 Sep 1;119(Pt 17):3551-60
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   Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2. The Journal of biological chemistry 2000 Dec 15;275(50):39741-6
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    The inhibitor ABIN-2 disrupts the interaction of receptor-interacting protein with the kinase subunit IKKgamma to block activation of the transcription factor NF-kappaB and potentiate apoptosis. The Biochemical journal 2004 Mar 15;378(Pt 3):867-76
13. Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K
    Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 1999 Jan 7;18(1):1-8
14. Tian H, McKnight SL, Russell DW
    Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & development 1997 Jan 1;11(1):72-82
15. Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, Manabe I, Nagai R
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16. Dube A, Akbarali Y, Sato TN, Libermann TA, Oettgen P
    Role of the Ets transcription factors in the regulation of the vascular-specific Tie2 gene. Circulation research 1999 May 28;84(10):1177-85