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, sTIE2, sTEK)

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 sTEK 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
• soluble TEK (sTEK) may be a biomarker of frailty

Pharmacology

• may play a role in mechanism of mesenchymal stem cell therapy (laromestrocel)

More general terms

• tyrosine kinase receptor (RTK)
• glycoprotein
• human longevity protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=7010
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:7010
• OMIM: https://mirror.omim.org/entry/600195
• OMIM: https://mirror.omim.org/entry/600221
• UniProt: http://www.uniprot.org/uniprot/Q02763.html