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Protein

Angiopoietin-1 receptor

Gene

Tek

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 TIE1.7 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation1 Publication

Enzyme regulationi

Angiopoietin binding leads to receptor dimerization and activation by autophosphorylation at Tyr-990 on the kinase activation loop.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei853ATPPROSITE-ProRule annotation1
Active sitei962Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi828 – 836ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • growth factor binding Source: MGI
  • protein tyrosine kinase activity Source: UniProtKB
  • signaling receptor activity Source: MGI
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB-EC

GO - Biological processi

  • angiogenesis Source: UniProtKB
  • branching involved in blood vessel morphogenesis Source: DFLAT
  • cell-cell adhesion Source: MGI
  • cell-matrix adhesion Source: MGI
  • endothelial cell proliferation Source: UniProtKB
  • glomerulus vasculature development Source: MGI
  • heart development Source: UniProtKB
  • heart trabecula formation Source: UniProtKB
  • hemopoiesis Source: MGI
  • intracellular signal transduction Source: MGI
  • negative regulation of angiogenesis Source: UniProtKB
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of endothelial cell apoptotic process Source: UniProtKB
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • positive regulation of actin cytoskeleton reorganization Source: MGI
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of cell adhesion Source: MGI
  • positive regulation of cytokine secretion involved in immune response Source: MGI
  • positive regulation of endothelial cell migration Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of focal adhesion assembly Source: UniProtKB
  • positive regulation of intracellular signal transduction Source: UniProtKB
  • positive regulation of peptidyl-serine phosphorylation Source: MGI
  • positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • positive regulation of protein import into nucleus Source: MGI
  • positive regulation of protein kinase B signaling Source: UniProtKB
  • positive regulation of protein phosphorylation Source: MGI
  • positive regulation of vascular endothelial growth factor receptor signaling pathway Source: DFLAT
  • protein autophosphorylation Source: UniProtKB
  • protein complex oligomerization Source: MGI
  • regulation of angiogenesis Source: MGI
  • regulation of cell migration Source: MGI
  • regulation of endothelial cell proliferation Source: DFLAT
  • regulation of establishment or maintenance of cell polarity Source: UniProtKB
  • regulation of NIK/NF-kappaB signaling Source: MGI
  • response to estrogen Source: MGI
  • response to retinoic acid Source: BHF-UCL
  • sprouting angiogenesis Source: UniProtKB
  • substrate adhesion-dependent cell spreading Source: UniProtKB
  • Tie signaling pathway Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: UniProtKB
  • vasculogenesis Source: UniProtKB

Keywordsi

Molecular functionKinase, Receptor, Transferase, Tyrosine-protein kinase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1 3474
ReactomeiR-MMU-210993 Tie2 Signaling
R-MMU-5673001 RAF/MAP kinase cascade

Names & Taxonomyi

Protein namesi
Recommended name:
Angiopoietin-1 receptor (EC:2.7.10.1)
Alternative name(s):
Endothelial tyrosine kinase
HYK
STK1
Tunica interna endothelial cell kinase
Tyrosine kinase with Ig and EGF homology domains-2
Tyrosine-protein kinase receptor TEK
Tyrosine-protein kinase receptor TIE-2
Short name:
mTIE2
p140 TEK
CD_antigen: CD202b
Gene namesi
Name:Tek
Synonyms:Hyk, Tie-2, Tie2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:98664 Tek

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini23 – 746ExtracellularSequence analysisAdd BLAST724
Transmembranei747 – 767HelicalSequence analysisAdd BLAST21
Topological domaini768 – 1122CytoplasmicSequence analysisAdd BLAST355

Keywords - Cellular componenti

Cell junction, Cell membrane, Cytoplasm, Cytoskeleton, Membrane, Secreted

Pathology & Biotechi

Disruption phenotypei

Embryonically lethal. Embryos die at about 10 dpc, due to strongly decreased numbers of blood vessel endothelial cells, leading to severe hemorrhaging, and due to defects in heart trabeculae development. Mice display a general malformation of the vascular network with defective sprouting and dilated blood vessels. Conditional by inversion allele knockout mice don't have Schlemm's canal. Haploinsufficient mice developed a severely hypomorphic Schlemm's canal with convolutions and focal narrowing (PubMed:27270174).3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi853K → A: Loss of kinase activity. 2 Publications1
Mutagenesisi1100Y → F: Reduced levels of autophosphorylation. Abolishes interaction with GRB2 and GRB7. Abolishes phosphorylation of GRB7 and PIK3R1. 3 Publications1
Mutagenesisi1106Y → F: Reduced levels of autophosphorylation. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL5199

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 22By similarityAdd BLAST22
ChainiPRO_000002447523 – 1122Angiopoietin-1 receptorAdd BLAST1100

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi44 ↔ 102By similarity
Glycosylationi140N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi158N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi211 ↔ 220By similarity
Disulfide bondi224 ↔ 233By similarity
Disulfide bondi227 ↔ 240By similarity
Disulfide bondi242 ↔ 251By similarity
Disulfide bondi255 ↔ 264By similarity
Disulfide bondi268 ↔ 274By similarity
Disulfide bondi280 ↔ 287By similarity
Disulfide bondi289 ↔ 298By similarity
Disulfide bondi302 ↔ 311By similarity
Disulfide bondi315 ↔ 323By similarity
Disulfide bondi317 ↔ 329By similarity
Disulfide bondi331 ↔ 340By similarity
Disulfide bondi370 ↔ 424By similarity
Glycosylationi399N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi438N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi464N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi558N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi595N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi648N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi690N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei858Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei990Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1100Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1106Phosphotyrosine; by autocatalysis1 Publication1

Post-translational modificationi

Proteolytic processing leads to the shedding of the extracellular domain (soluble TIE-2 alias sTIE-2).By similarity
Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Autophosphorylation occurs in a sequential manner, where Tyr-990 in the kinase activation loop is phosphorylated first, followed by autophosphorylation at Tyr-1106 and at additional tyrosine residues. ANGPT1-induced phosphorylation is impaired during hypoxia, due to increased expression of ANGPT2 (By similarity). Phosphorylation is important for interaction with GRB14, PIK3R1 and PTPN11. Phosphorylation at Tyr-1100 is important for interaction with GRB2 and GRB7. Phosphorylation at Tyr-1106 is important for interaction with DOK2 and for coupling to downstream signal transduction pathways in endothelial cells. Dephosphorylated by PTPRB.By similarity2 Publications
Ubiquitinated. The phosphorylated receptor is ubiquitinated and internalized, leading to its degradation (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ02858
PaxDbiQ02858
PRIDEiQ02858

PTM databases

iPTMnetiQ02858
PhosphoSitePlusiQ02858

Expressioni

Tissue specificityi

Specifically expressed in developing vascular endothelial cells. Abundantly expressed in lung and heart, moderately in brain, liver and kidney, and weakly in thymus, spleen and testis.1 Publication

Developmental stagei

Expression detectable in day 8.5 embryos.

Gene expression databases

BgeeiENSMUSG00000006386
CleanExiMM_TEK
ExpressionAtlasiQ02858 baseline and differential
GenevisibleiQ02858 MM

Interactioni

Subunit structurei

Homodimer. Heterodimer with TIE1. Interacts with ANGPT1, ANGPT2 and 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 (tyrosine phosphorylated) with TNIP2. Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain) (By similarity). Interacts with PTPRB; this promotes endothelial cell-cell adhesion. Interacts with DOK2, GRB2, GRB7, GRB14, PIK3R1 and PTPN11/SHP2. Colocalizes with DOK2 at contacts with the extracellular matrix in migrating cells.By similarity7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204107, 5 interactors
IntActiQ02858, 7 interactors
MINTiQ02858
STRINGi10090.ENSMUSP00000099862

Chemistry databases

BindingDBiQ02858

Structurei

3D structure databases

ProteinModelPortaliQ02858
SMRiQ02858
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini44 – 123Ig-like C2-type 1Add BLAST80
Domaini210 – 252EGF-like 1PROSITE-ProRule annotationAdd BLAST43
Domaini254 – 299EGF-like 2PROSITE-ProRule annotationAdd BLAST46
Domaini301 – 341EGF-like 3PROSITE-ProRule annotationAdd BLAST41
Domaini350 – 440Ig-like C2-type 2Add BLAST91
Domaini444 – 539Fibronectin type-III 1PROSITE-ProRule annotationAdd BLAST96
Domaini543 – 635Fibronectin type-III 2PROSITE-ProRule annotationAdd BLAST93
Domaini640 – 733Fibronectin type-III 3PROSITE-ProRule annotationAdd BLAST94
Domaini822 – 1094Protein kinasePROSITE-ProRule annotationAdd BLAST273

Domaini

The soluble extracellular domain is functionally active in angiopoietin binding and can modulate the activity of the membrane-bound form by competing for angiopoietins.By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Tie subfamily.PROSITE-ProRule annotation

Keywords - Domaini

EGF-like domain, Immunoglobulin domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00810000125384
HOGENOMiHOG000049232
HOVERGENiHBG007316
InParanoidiQ02858
KOiK05121

Family and domain databases

CDDicd00063 FN3, 2 hits
Gene3Di2.60.40.10, 6 hits
InterProiView protein in InterPro
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR003961 FN3_dom
IPR036116 FN3_sf
IPR007110 Ig-like_dom
IPR036179 Ig-like_dom_sf
IPR013783 Ig-like_fold
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR018941 Tyr_kin_Tie2_Ig-like_dom-1_N
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
PfamiView protein in Pfam
PF00041 fn3, 3 hits
PF10430 Ig_Tie2_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00181 EGF, 2 hits
SM00060 FN3, 3 hits
SM00220 S_TKc, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF48726 SSF48726, 1 hit
SSF49265 SSF49265, 2 hits
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00022 EGF_1, 3 hits
PS01186 EGF_2, 3 hits
PS50026 EGF_3, 1 hit
PS50853 FN3, 3 hits
PS50835 IG_LIKE, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q02858-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDSLAGLVLC GVSLLLYGVV EGAMDLILIN SLPLVSDAET SLTCIASGWH
60 70 80 90 100
PHEPITIGRD FEALMNQHQD PLEVTQDVTR EWAKKVVWKR EKASKINGAY
110 120 130 140 150
FCEGRVRGQA IRIRTMKMRQ QASFLPATLT MTVDRGDNVN ISFKKVLIKE
160 170 180 190 200
EDAVIYKNGS FIHSVPRHEV PDILEVHLPH AQPQDAGVYS ARYIGGNLFT
210 220 230 240 250
SAFTRLIVRR CEAQKWGPDC SRPCTTCKNN GVCHEDTGEC ICPPGFMGRT
260 270 280 290 300
CEKACEPHTF GRTCKERCSG PEGCKSYVFC LPDPYGCSCA TGWRGLQCNE
310 320 330 340 350
ACPSGYYGPD CKLRCHCTNE EICDRFQGCL CSQGWQGLQC EKEGRPRMTP
360 370 380 390 400
QIEDLPDHIE VNSGKFNPIC KASGWPLPTS EEMTLVKPDG TVLQPNDFNY
410 420 430 440 450
TDRFSVAIFT VNRVLPPDSG VWVCSVNTVA GMVEKPFNIS VKVLPEPLHA
460 470 480 490 500
PNVIDTGHNF AIINISSEPY FGDGPIKSKK LFYKPVNQAW KYIEVTNEIF
510 520 530 540 550
TLNYLEPRTD YELCVQLARP GEGGEGHPGP VRRFTTASIG LPPPRGLSLL
560 570 580 590 600
PKSQTALNLT WQPIFTNSED EFYVEVERRS LQTTSDQQNI KVPGNLTSVL
610 620 630 640 650
LSNLVPREQY TVRARVNTKA QGEWSEELRA WTLSDILPPQ PENIKISNIT
660 670 680 690 700
DSTAMVSWTI VDGYSISSII IRYKVQGKNE DQHIDVKIKN ATVTQYQLKG
710 720 730 740 750
LEPETTYHVD IFAENNIGSS NPAFSHELRT LPHSPASADL GGGKMLLIAI
760 770 780 790 800
LGSAGMTCIT VLLAFLIMLQ LKRANVQRRM AQAFQNREEP AVQFNSGTLA
810 820 830 840 850
LNRKAKNNPD PTIYPVLDWN DIKFQDVIGE GNFGQVLKAR IKKDGLRMDA
860 870 880 890 900
AIKRMKEYAS KDDHRDFAGE LEVLCKLGHH PNIINLLGAC EHRGYLYLAI
910 920 930 940 950
EYAPHGNLLD FLRKSRVLET DPAFAIANST ASTLSSQQLL HFAADVARGM
960 970 980 990 1000
DYLSQKQFIH RDLAARNILV GENYIAKIAD FGLSRGQEVY VKKTMGRLPV
1010 1020 1030 1040 1050
RWMAIESLNY SVYTTNSDVW SYGVLLWEIV SLGGTPYCGM TCAELYEKLP
1060 1070 1080 1090 1100
QGYRLEKPLN CDDEVYDLMR QCWREKPYER PSFAQILVSL NRMLEERKTY
1110 1120
VNTTLYEKFT YAGIDCSAEE AA
Length:1,122
Mass (Da):125,701
Last modified:February 1, 1995 - v2
Checksum:iF879623D103FFE96
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti161 – 171FIHSVPRHEVP → LHPLSAPGMKYL in BAA02883 (PubMed:1282811).CuratedAdd BLAST11
Sequence conflicti538S → C in CAA47857 (PubMed:8386827).Curated1
Sequence conflicti736A → G in CAA47857 (PubMed:8386827).Curated1
Sequence conflicti736A → G in AAB28663 (PubMed:8217221).Curated1
Sequence conflicti745 – 761MLLIA…TCITV → DATHSHPWVWNDFASPC in BAA02883 (PubMed:1282811).CuratedAdd BLAST17
Sequence conflicti786N → NV in BAA02883 (PubMed:1282811).Curated1
Sequence conflicti786N → NV no nucleotide entry (PubMed:8395828).Curated1
Sequence conflicti913R → G in BAA02883 (PubMed:1282811).Curated1
Sequence conflicti925 – 931AIANSTA → CHRQQYS in BAA02883 (PubMed:1282811).Curated7
Sequence conflicti1117S → P in BAA02883 (PubMed:1282811).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X71426 mRNA Translation: CAA50557.1
X67553 mRNA Translation: CAA47857.1
D13738 mRNA Translation: BAA02883.1
S67051 mRNA Translation: AAB28663.1
CCDSiCCDS71421.1
PIRiI54237
JH0771
JN0712
RefSeqiNP_001277478.1, NM_001290549.1
UniGeneiMm.14313

Genome annotation databases

EnsembliENSMUST00000071168; ENSMUSP00000071162; ENSMUSG00000006386
GeneIDi21687
KEGGimmu:21687
UCSCiuc008tsk.2 mouse

Similar proteinsi

Entry informationi

Entry nameiTIE2_MOUSE
AccessioniPrimary (citable) accession number: Q02858
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: February 1, 1995
Last modified: June 20, 2018
This is version 180 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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