TIE2_BOVIN
ID TIE2_BOVIN Reviewed; 1125 AA.
AC Q06807;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Angiopoietin-1 receptor;
DE EC=2.7.10.1;
DE AltName: Full=Endothelial tyrosine kinase;
DE AltName: Full=Tyrosine kinase with Ig and EGF homology domains-2;
DE AltName: Full=Tyrosine-protein kinase receptor TIE-2;
DE AltName: CD_antigen=CD202b;
DE Flags: Precursor;
GN Name=TEK; Synonyms=TIE-2, TIE2;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Endothelial cell;
RX PubMed=8415706; DOI=10.1073/pnas.90.20.9355;
RA Sato T.N., Qin Y., Kozak C.A., Andus K.L.;
RT "Tie-1 and tie-2 define another class of putative receptor tyrosine kinase
RT genes expressed in early embryonic vascular system.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9355-9358(1993).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor
CC for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial
CC cell survival, proliferation, migration, adhesion and cell spreading,
CC reorganization of the actin cytoskeleton, but also maintenance of
CC vascular quiescence. Has anti-inflammatory effects by preventing the
CC leakage of pro-inflammatory plasma proteins and leukocytes from blood
CC vessels. Required for normal angiogenesis and heart development during
CC embryogenesis. Required for post-natal hematopoiesis. After birth,
CC activates or inhibits angiogenesis, depending on the context. Inhibits
CC angiogenesis and promotes vascular stability in quiescent vessels,
CC where endothelial cells have tight contacts. In quiescent vessels,
CC ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes
CC with TEK molecules from adjoining cells, and this leads to preferential
CC activation of phosphatidylinositol 3-kinase and the AKT1 signaling
CC cascades. In migrating endothelial cells that lack cell-cell adhesions,
CC ANGT1 recruits TEK to contacts with the extracellular matrix, leading
CC to the formation of focal adhesion complexes, activation of PTK2/FAK
CC and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately
CC to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers
CC receptor dimerization and autophosphorylation at specific tyrosine
CC residues that then serve as binding sites for scaffold proteins and
CC effectors. Signaling is modulated by ANGPT2 that has lower affinity for
CC TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but
CC inhibits ANGPT1-mediated signaling by competing for the same binding
CC site. Signaling is also modulated by formation of heterodimers with
CC TIE1, and by proteolytic processing that gives rise to a soluble TEK
CC extracellular domain. The soluble extracellular domain modulates
CC signaling by functioning as decoy receptor for angiopoietins. TEK
CC phosphorylates DOK2, GRB7, GRB14, PIK3R1, SHC1 and TIE1 (By
CC similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Angiopoietin binding leads to receptor
CC dimerization and activation by autophosphorylation at Tyr-993 on the
CC kinase activation loop. {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Heterodimer with TIE1. Interacts with ANGPT1,
CC ANGPT2 and ANGPT4. At cell-cell contacts in quiescent cells, forms a
CC signaling complex composed of ANGPT1 plus TEK molecules from two
CC adjoining cells. In the absence of endothelial cell-cell contacts,
CC interaction with ANGPT1 mediates contacts with the extracellular
CC matrix. Interacts (tyrosine phosphorylated) with TNIP2. Interacts
CC (tyrosine phosphorylated) with SHC1 (via SH2 domain) (By similarity).
CC Interacts with PTPRB; this promotes endothelial cell-cell adhesion.
CC Interacts with DOK2, GRB2, GRB7, GRB14, PIK3R1 and PTPN11/SHP2.
CC Colocalizes with DOK2 at contacts with the extracellular matrix in
CC migrating cells (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}. Cell junction {ECO:0000250}. Cell
CC junction, focal adhesion {ECO:0000250}. Cytoplasm, cytoskeleton
CC {ECO:0000250}. Secreted {ECO:0000250}. Note=Recruited to cell-cell
CC contacts in quiescent endothelial cells. Colocalizes with the actin
CC cytoskeleton and at actin stress fibers during cell spreading.
CC Recruited to the lower surface of migrating cells, especially the rear
CC end of the cell. Proteolytic processing gives rise to a soluble
CC extracellular domain that is secreted (By similarity). {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Specifically expressed in developing vascular
CC endothelial cells.
CC -!- DOMAIN: The soluble extracellular domain is functionally active in
CC angiopoietin binding and can modulate the activity of the membrane-
CC bound form by competing for angiopoietins. {ECO:0000250}.
CC -!- PTM: Proteolytic processing leads to the shedding of the extracellular
CC domain (soluble TIE-2 alias sTIE-2). {ECO:0000250}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to ligand
CC binding. Autophosphorylation occurs in trans, i.e. one subunit of the
CC dimeric receptor phosphorylates tyrosine residues on the other subunit.
CC Autophosphorylation occurs in a sequential manner, where Tyr-993 in the
CC kinase activation loop is phosphorylated first, followed by
CC autophosphorylation at Tyr-1109 and at additional tyrosine residues.
CC ANGPT1-induced phosphorylation is impaired during hypoxia, due to
CC increased expression of ANGPT2 (By similarity). Phosphorylation is
CC important for interaction with GRB14, PIK3R1 and PTPN11.
CC Phosphorylation at Tyr-1103 is important for interaction with GRB2 and
CC GRB7. Phosphorylation at Tyr-1109 is important for interaction with
CC DOK2 and for coupling to downstream signal transduction pathways in
CC endothelial cells. Dephosphorylated by PTPRB (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Ubiquitinated. The phosphorylated receptor is ubiquitinated and
CC internalized, leading to its degradation (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Tie subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; X71424; CAA50555.1; -; mRNA.
DR PIR; S57846; S57846.
DR RefSeq; NP_776389.1; NM_173964.2.
DR AlphaFoldDB; Q06807; -.
DR SMR; Q06807; -.
DR STRING; 9913.ENSBTAP00000026836; -.
DR PaxDb; Q06807; -.
DR PeptideAtlas; Q06807; -.
DR PRIDE; Q06807; -.
DR Ensembl; ENSBTAT00000026836; ENSBTAP00000026836; ENSBTAG00000020148.
DR GeneID; 280939; -.
DR KEGG; bta:280939; -.
DR CTD; 7010; -.
DR VEuPathDB; HostDB:ENSBTAG00000020148; -.
DR VGNC; VGNC:35735; TEK.
DR eggNOG; KOG0200; Eukaryota.
DR GeneTree; ENSGT00940000158840; -.
DR HOGENOM; CLU_008888_0_0_1; -.
DR InParanoid; Q06807; -.
DR OMA; PEGITLF; -.
DR OrthoDB; 707342at2759; -.
DR TreeFam; TF317568; -.
DR BRENDA; 2.7.10.1; 908.
DR Proteomes; UP000009136; Chromosome 8.
DR Bgee; ENSBTAG00000020148; Expressed in lung and 104 other tissues.
DR ExpressionAtlas; Q06807; baseline and differential.
DR GO; GO:0005884; C:actin filament; IEA:Ensembl.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR GO; GO:0034451; C:centriolar satellite; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005902; C:microvillus; IEA:Ensembl.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0001725; C:stress fiber; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0001525; P:angiogenesis; ISS:UniProtKB.
DR GO; GO:0001935; P:endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0060347; P:heart trabecula formation; ISS:UniProtKB.
DR GO; GO:0016525; P:negative regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:2000251; P:positive regulation of actin cytoskeleton reorganization; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; ISS:UniProtKB.
DR GO; GO:1902533; P:positive regulation of intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IBA:GO_Central.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0032878; P:regulation of establishment or maintenance of cell polarity; ISS:UniProtKB.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; ISS:UniProtKB.
DR GO; GO:0048014; P:Tie signaling pathway; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB.
DR CDD; cd00055; EGF_Lam; 2.
DR CDD; cd00063; FN3; 2.
DR Gene3D; 2.60.40.10; -; 6.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR002049; LE_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR018941; Tyr_kin_Tie2_Ig-like_dom-1_N.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR Pfam; PF00041; fn3; 3.
DR Pfam; PF10430; Ig_Tie2_1; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00181; EGF; 2.
DR SMART; SM00060; FN3; 3.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00022; EGF_1; 3.
DR PROSITE; PS01186; EGF_2; 2.
DR PROSITE; PS50026; EGF_3; 1.
DR PROSITE; PS50853; FN3; 3.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell junction; Cell membrane; Cytoplasm; Cytoskeleton;
KW Disulfide bond; EGF-like domain; Glycoprotein; Immunoglobulin domain;
KW Kinase; Membrane; Nucleotide-binding; Phosphoprotein; Receptor;
KW Reference proteome; Repeat; Secreted; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..22
FT /evidence="ECO:0000250"
FT CHAIN 23..1125
FT /note="Angiopoietin-1 receptor"
FT /id="PRO_0000024473"
FT TOPO_DOM 23..748
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 749..769
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 770..1125
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 44..123
FT /note="Ig-like C2-type 1"
FT DOMAIN 210..252
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 254..299
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 301..341
FT /note="EGF-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 350..440
FT /note="Ig-like C2-type 2"
FT DOMAIN 447..541
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 545..637
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 642..735
FT /note="Fibronectin type-III 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 825..1097
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ACT_SITE 965
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 831..839
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 856
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 861
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q02763"
FT MOD_RES 993
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q02763"
FT MOD_RES 1103
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q02763"
FT MOD_RES 1109
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q02763"
FT CARBOHYD 158
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 44..102
FT /evidence="ECO:0000250"
FT DISULFID 211..220
FT /evidence="ECO:0000250"
FT DISULFID 224..233
FT /evidence="ECO:0000250"
FT DISULFID 227..240
FT /evidence="ECO:0000250"
FT DISULFID 242..251
FT /evidence="ECO:0000250"
FT DISULFID 255..264
FT /evidence="ECO:0000250"
FT DISULFID 268..274
FT /evidence="ECO:0000250"
FT DISULFID 280..287
FT /evidence="ECO:0000250"
FT DISULFID 289..298
FT /evidence="ECO:0000250"
FT DISULFID 302..311
FT /evidence="ECO:0000250"
FT DISULFID 315..323
FT /evidence="ECO:0000250"
FT DISULFID 317..329
FT /evidence="ECO:0000250"
FT DISULFID 331..340
FT /evidence="ECO:0000250"
FT DISULFID 370..424
FT /evidence="ECO:0000250"
SQ SEQUENCE 1125 AA; 125927 MW; 015F1320AB853B7F CRC64;
MDSLAGLVLC GVSLLLSATV DGAMDLILIN SLPLVSDAET SLTCIASGWR PHEPITIGRD
FEALMNQHQD PLEVTQDATR EWAKKVVWKR EKASKINGAY FCEGRVRGQA IRIRTMKMRQ
QASFLPATLT MTVDRGDNVN ISFKKVLIKE EDAVIYKNGS FIHSVPRHEV PDILEVQVPH
AQPQDAGVYS ARYIGGNLFT SAFTRLIVRR CEAQKWGPEC NRICTACMNN GICHEDTGEC
ICPPGFMGRT CEKACEPHTF GRTCKERCSE PEGCKSFVFC LPDPYGCSCA TGWKGLQCNE
ACQPGYYGPD CKLRCSCTNG EKCDRFQGCL CSPGRQGLQC EKEGVPRMTP KIEDLPDHIE
VNSGKFNPIC KASGWPRPAN EEMTLVKPDG TVLRPKDFNH TGHLSVATFT INRILPPDSG
VWVCSVNTVS GMVEKPFNIS VKVLPKPLNA PKVIDTGHNF AVINISSEPY FGDGPIKSKK
LLYKPVNHYE AWRHIQVTNE IVTLNYLEPR TEYELCVQLV RRGEGGEGHP GPVRRFTTAS
IGLPPPRGLS LLPKSQTTLN LTWQPIFPSS EDDFYVEVER RSVQMNSDQQ NIKVPGNLTS
VLLNNLHPRE QYIVRARVNT KAQGEWSEDL IAWTLSDIVP PQPENIKIFN ITDSSAVISW
TILDGYSISA IIIRYKVQGK NEDQHIDVKI KNATITQYQL KGLEPQTVYQ VDIFAENNIG
SSNPTSSHEL TTLSESQAPA DLGGRKMLLI AILGSAGMTC LTVLLAFLIM LQLKRANVQR
RMAQAFQNVR EEPAVQFNSG TLALNRKAKN NPDPTIYPVL DWNDIKFQDV IGEGNFGQVL
KARIKKDGLR MDAAIKRMKE YASKDDHRDF AGELEVLCKL GHHPNIINLL GACEHRGYLY
LAIEYAPHGN LLDFLRKSRV LETDPAFAIA NSTASTLSSQ QLLHFAADVA RGMDYLSQKQ
FIHRDLAARN ILVGENYVAK IADFGLSRGQ EVYVKKTMGR LPVRWMAIES LNYSVYTTNS
DVWSYGVLLW EIVSLGGTPY CGMTCAELYE KLPQGYRLEK PLNCDDEVYD LMRQCWREKP
YERPSFAQIL VSLNRMLEER KTYVNTTLYE KFTYAGIDCS AEEAA
