angiopoietin-1 receptor; tyrosine-protein kinase receptor TIE-2; hTIE2; tyrosine-protein kinase receptor TEK; tunica interna endothelial cell kinase; p140 TEK; CD202b (TEK, TIE2)
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Function
- protein tyrosine-kinase transmembrane receptor for ANGPT1, ANGPT2 & ANGPT4
- may constitute earliest mammalian endothelial cell lineage marker
- regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion & cell spreading, reorganization of the actin cytoskeleton, & also maintenance of vascular quiescence
- has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins & leukocytes from blood vessels
- required for normal angiogenesis & heart development during embryogenesis
- required for post- natal hematopoiesis
- after birth, activates or inhibits angiogenesis, depending on the context
- inhibits angiogenesis & promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts
- in quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, & this leads to preferential activation of phosphatidylinositol 3-kinase & AKT1 signaling cascades
- in migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK & of the downstream kinases MAPK1/ERK2 & MAPK3/ERK1, & ultimately to stimulation of sprouting angiogenesis
- ANGPT1 signaling triggers receptor dimerization & autophosphorylation at specific Tyr that then serve as binding sites for scaffold proteins & effectors
- signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site
- signaling is also modulated by formation of heterodimers with TIE1, & by proteolytic processing that gives rise to a soluble TEK extracellular domain
- the soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins
- TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 & TIE1
- angiopoietin binding leads to receptor dimerization & activation by autophosphorylation at Tyr-992 on the kinase activation loop.
- proteolytic processing leads to the shedding of the extracellular domain (soluble TIE-2 alias sTIE-2)
- autophosphorylated on Tyr in response to ligand binding
- autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates Tyr on the other subunit
- autophosphorylation occurs in a sequential manner, where Tyr-992 in the kinase activation loop is phosphorylated first, followed by autophosphorylation at Tyr-1108 & at additional Tyr
- ANGPT1-induced phosphorylation is impaired during hypoxia, due to increased expression of ANGPT2
- phosphorylation is important for interaction with GRB14, PIK3R1 & PTPN11
- phosphorylation at Tyr-1102 is important for interaction with SHC1, GRB2 & GRB7
- phosphorylation at Tyr-1108 is important for interaction with DOK2 & for coupling to downstream signal transduction pathways in endothelial cells
- dephosphorylated by PTPRB
- ubiquitinated
- phosphorylated receptor is ubiquitinated & internalized, leading to its degradation
- homodimer. heterodimer with TIE1
- interacts with ANGPT1, ANGPT2 & ANGPT4
- at cell-cell contacts in quiescent cells, forms a signaling complex composed of ANGPT1 plus TEK molecules from two adjoining cells
- in the absence of endothelial cell-cell contacts, interaction with ANGPT1 mediates contacts with the extracellular matrix
- interacts with PTPRB; this promotes endothelial cell-cell adhesion
- interacts with DOK2, GRB2, GRB7, GRB14, PIK3R1 & PTPN11/SHP2
- colocalizes with DOK2 at contacts with the extracellular matrix in migrating cells
- interacts (Tyr phosphorylated) with TNIP2
- interacts (Tyr phosphorylated) with SHC1 (via SH2 domain)
Inhibition:
- inhibited by staurosporine, K252a, PP2, damnacanthal, SB203580, CEP-11207, CEP-11981 & CE-245677
- inhibited by triazine, thienopyrimidine & thiazolopyrimidine derivatives
Structure
- belongs to the protein kinase superfamily, Tyr protein kinase family, Tie subfamily
- contains 3 EGF-like domains
- contains 3 fibronectin F3 modules
- contains 2 Ig-like C2-type domains (immunoglobulin-like)
- contains 1 protein kinase domain
Compartment
- plasma membrane
- cell junction, focal adhesion
- cytoplasm, cytoskeleton
- secreted
- recruited to cell-cell contacts in quiescent endothelial cells
- colocalizes with the actin cytoskeleton & at actin stress fibers during cell spreading
- recruited to the lower surface of migrating cells, especially the rear end of the cell
- proteolytic processing gives rise to a soluble extracellular domain that is secreted
Alternative splicing
named isoforms=3
Expression
- predominantly expressed in endothelial cells & their progenitors, the angioblasts
- expressed in placenta & lung > umbilical vein endothelial cells, brain & kidney
Pathology
- defects in TEK are a cause of dominantly inherited venous malformations
- may play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis & inflammation