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 . But as well
Angiopoietin 2 was shown to be a partial agonist of
Tie2 and induces its internalization .
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
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
- Jones N, Iljin K, Dumont DJ, Alitalo K
Tie receptors: new modulators of angiogenic and lymphangiogenic responses.
Nature reviews. Molecular cell biology 2001 Apr;2(4):257-67
- Bogdanovic E, Nguyen VP, Dumont DJ
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
- Marron MB, Hughes DP, Edge MD, Forder CL, Brindle NP
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
- Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ
Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration.
The Journal of biological chemistry 1999 Oct 22;274(43):30896-905
- Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, Dewhirst MW, Sankar S
Functional significance of Tie2 signaling in the adult vasculature.
Recent progress in hormone research 2004;59:51-71
- Master Z, Jones N, Tran J, Jones J, Kerbel RS, Dumont DJ
Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak.
The EMBO journal 2001 Nov 1;20(21):5919-28
- Jones N, Dumont DJ
The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R.
Oncogene 1998 Sep 3;17(9):1097-108
- Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O'Connor DS, Li F, Altieri DC, Sessa WC
Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway.
The Journal of biological chemistry 2000 Mar 31;275(13):9102-5
- Daly C, Wong V, Burova E, Wei Y, Zabski S, Griffiths J, Lai KM, Lin HC, Ioffe E, Yancopoulos GD, Rudge JS
Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1).
Genes & development 2004 May 1;18(9):1060-71
- Hughes DP, Marron MB, Brindle NP
The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2.
Circulation research 2003 Apr 4;92(6):630-6
- Tadros A, Hughes DP, Dunmore BJ, Brindle NP
ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1.
Blood 2003 Dec 15;102(13):4407-9
- Liu WK, Yen PF, Chien CY, Fann MJ, Su JY, Chou CK
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
- 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
- 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
- Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, Manabe I, Nagai R
Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1.
Circulation research 2004 Jul 23;95(2):146-53
- 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