InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: TEK

Summary

InnateDB Protein

IDBP-294896.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

TEK

Protein Name

TEK tyrosine kinase, endothelial

Synonyms

CD202B; TIE-2; TIE2; VMCM; VMCM1;

Species

Homo sapiens

Ensembl Protein

ENSP00000383977

InnateDB Gene

IDBG-55143 (TEK)

Protein Structure

UniProt Annotation

Function

Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and 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, and this leads to preferential activation of phosphatidylinositol 3-kinase and the 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 and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and 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, and 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 and TIE1. {ECO:0000269PubMed:12816861, ECO:0000269PubMed:14665640, ECO:0000269PubMed:15284220, ECO:0000269PubMed:15851516, ECO:0000269PubMed:18366015, ECO:0000269PubMed:18425119, ECO:0000269PubMed:18425120, ECO:0000269PubMed:19223473, ECO:0000269PubMed:20651738, ECO:0000269PubMed:9204896}.

Subcellular Localization

Cell membrane; Single-pass type I membrane protein. Cell junction. Cell junction, focal adhesion. Cytoplasm, cytoskeleton. Secreted. Note=Recruited to cell-cell contacts in quiescent endothelial cells. Colocalizes with the actin cytoskeleton and 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.

Disease Associations

Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269PubMed:10369874, ECO:0000269PubMed:19888299, ECO:0000269PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry.Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.

Tissue Specificity

Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. {ECO:0000269PubMed:11806244, ECO:0000269PubMed:8382358}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 29 experimentally validated interaction(s) in this database.
They are also associated with 11 interaction(s) predicted by orthology.

Experimentally validated
Total	29 [view]
Protein-Protein	29 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	11 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0004872	receptor activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups

Biological Process

GO:0001525	angiogenesis
GO:0001934	positive regulation of protein phosphorylation
GO:0001935	endothelial cell proliferation
GO:0001938	positive regulation of endothelial cell proliferation
GO:0002040	sprouting angiogenesis
GO:0006468	protein phosphorylation
GO:0007165	signal transduction
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007267	cell-cell signaling
GO:0007507	heart development
GO:0007596	blood coagulation
GO:0010595	positive regulation of endothelial cell migration
GO:0014068	positive regulation of phosphatidylinositol 3-kinase signaling
GO:0016525	negative regulation of angiogenesis
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0032878	regulation of establishment or maintenance of cell polarity
GO:0034446	substrate adhesion-dependent cell spreading
GO:0043066	negative regulation of apoptotic process
GO:0043114	regulation of vascular permeability
GO:0043552	positive regulation of phosphatidylinositol 3-kinase activity
GO:0045766	positive regulation of angiogenesis
GO:0046777	protein autophosphorylation
GO:0048014	Tie signaling pathway
GO:0050728	negative regulation of inflammatory response
GO:0050900	leukocyte migration
GO:0051259	protein oligomerization
GO:0051894	positive regulation of focal adhesion assembly
GO:0051897	positive regulation of protein kinase B signaling
GO:0060216	definitive hemopoiesis
GO:0060347	heart trabecula formation
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:1902533	positive regulation of intracellular signal transduction
GO:2000251	positive regulation of actin cytoskeleton reorganization
GO:2000351	regulation of endothelial cell apoptotic process
GO:2000352	negative regulation of endothelial cell apoptotic process

Cellular Component

GO:0001725	stress fiber
GO:0005576	extracellular region
GO:0005737	cytoplasm
GO:0005884	actin filament
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005902	microvillus
GO:0005911	cell-cell junction
GO:0005925	focal adhesion
GO:0009925	basal plasma membrane
GO:0009986	cell surface
GO:0016323	basolateral plasma membrane
GO:0016324	apical plasma membrane
GO:0045121	membrane raft

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000742 Epidermal growth factor-like domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003961 Fibronectin, type III
IPR007110 Immunoglobulin-like domain
IPR011009 Protein kinase-like domain
IPR018941 Tyrosine-protein kinase, receptor Tie-2, Ig-like domain 1, N-terminal
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF00008
PF07714
PF00041
PF01108
PF10430

PRINTS

PR00109

PIRSF

SMART

SM00181
SM00220
SM00060
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt