TIE2 is a member of TIE receptor tyrosine kinase family that is well-known to regulate mainly the endothelial cell functions [1, 2]. Angiopoietins (angiopoietin-1, 2 and 4 in humans) are the best characterized ligands for TIE2 . Angiopoietin-1 (ANGPT1) is the known constitutive agonist of TIE2, while angiopoietin-2 (ANGPT2) is a context-dependent agonist or antagonist of TIE2 [4, 5] Angiopoietin-4 (ANGPT4) considered to be agonistic, its mouse ortholog, angiopoietin-3 (ANGPT3), is reported to be antagonistic to TIE2 . TIE1, the other member of the TIE family is an orphan receptor. However, TIE1 is known to heterodimerize with TIE2 and negatively regulate TIE2 signaling .
Binding of tetrameric or higher order oligomeric ANGPT1 leads to TIE2 dimerization and activation of the TIE2 tyrosine kinase activity followed by autophosphorylation (Y992, Y1102, Y1108 and Y1113) [8, 9]. Further, SH2 domain containing proteins such asgrowth 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) are recruited and transphosphorylated by TIE2 . GRB2 and SHC1 recruits SOS1 and lead to the activation of Ras-Raf-mitogen activated protein kinase (MAPK) pathway that regulate platelet activating factor synthesis, anti-inflammatory responses, endothelial cell migration, proliferation, permeability and morphogenesis [11, 12, 13, 14, 15, 16] . Through SOS1 or PI3Ks, angiopoietin/TIE2 system also regulates the activation of RAC1, RHOA, CDC42 and focal adhesion kinase 1 to mediate cytoskeleton reorganization and migration of endothelial and synovial cells . Angiopoietin 1 induced activation of RHOA results in sequestration of SRC by DIAPH1 thereby preventing SRC association with VEGFR2 . DOKs, especially, DOK2 recruits dynamic complexes comprising of NCK adaptor protein 1 (NCK1), RAS p21 protein activator 1 (p120GAP) and P21 protein-activated kinase 1 (PAK1) to TIE2 that lead to increased cell motility .
Downstream activation of PI3K/AKT inhibits Smac release from mitochondria and increases the expression of survivin which untimely controls the survival and chemotaxis in endothelial cells [20, 21]. AKT activation also inhibits forkhead transcription factor FKHR (FOXO1) which protects endothelial cells from apoptosis .ANGPT1 also induces the PI3K/AKT mediated activation of eNOS and NO release in endothelial cells [23, 24]. In endothelial cells, both ANGPT1 and ANGPT2 also induce TIE2-dependent translocation of P-Selectin through a PLCG1/ Ca2+ signaling pathway .
TIE2 also interacts with the inhibitor of Nuclear factor kappa B (NF-kB) activity TNFAIP3 interacting protein 2 (ABIN-2) that inhibits NF-kB transcriptional activity and mediates anti-inflammatory and anti-apoptotic action [26, 27].
TIE2 activation induces the phosphorylation of STAT1, STAT3 and STAT5A/5B and their subsequent translocation into nucleus to induce the expression of the cell cycle inhibitor Cyclin-dependent kinase inhibitor 1A (p21) .
ANGPT2 also interacts with integrins like integrin αVβ5, αVβ3 and α5β1 in endothelial cells with less affinity than TIE2 and can induceTIE2-independent signaling . TIE2 also forms a complex with α5β3 and FAK. ANGPT2 induces phosphorylation of FAK at serine 910, α5β3 internalization, and dissociation of p130CAS and Talin from α5β3 . Recently, ANGPT2 has also been shown to induce the activation of ERK/MSK1/CREB pathway to impart cell survival and resistance to doxorubin in HepG2 cells .
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