Pathway maps

Development_Angiopoietin - Tie2 signaling
Development_Angiopoietin - Tie2 signaling

Object List (links open in MetaCore):

PtdIns(3,4,5)P3, NF-KB, I-KB,, 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 [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 [2].

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 ) [3]. 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 [4].

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], [4]. DOK2 is also constitutively bound to v-crk sarcoma virus CT10 oncogene 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 of Baculoviral IAP repeat-containing 5 ( Survivin ), and thus protects endothelial cells from undergoing apoptosis [7], [8] and induces expression of 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, kinase gamma ( IKK-gamma ) [11]. Inhibition of NF-kB transcriptional activity 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 to be elucidated. Activated STAT induces the cell cycle inhibitor Cyclin-dependent kinase inhibitor 1A ( p21 ) expression [12].

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 [13], [14]. E74-like factor 2 ( Elf2 ) also promotes expression of Tie2 in vascular endothelial cells in the setting of hypoxia [15].


  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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