EzCatDB: M00325
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DB codeM00325
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 12.60.40.10 : Immunoglobulin-like
Domain 22.60.40.10 : Immunoglobulin-like
Domain 32.170.300.10
Domain 42.60.40.10 : Immunoglobulin-like
Domain 52.60.40.10 : Immunoglobulin-like
Domain 62.60.40.10 : Immunoglobulin-like
Domain 72.60.40.10 : Immunoglobulin-like
Domain 8-.-.-.-
Domain 9-.-.-.-
Domain 103.30.200.20 : Phosphorylase Kinase; domain 1
Domain 111.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
Domain 12-.-.-.-
E.C.2.7.10.1

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
2.60.40.10 : Immunoglobulin-likeM00131,T00257,T00005,M00113,M00127,M00132,M00323,M00327,M00329,M00330,M00331,M00332,T00307,D00166,D00500,M00112,M00193,T00063,T00065,T00067,T00245
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298

Enzyme Name
UniProtKBKEGG

Q02763
Protein nameAngiopoietin-1 receptor (EC 2.7.10.1) (Endothelial tyrosine kinase) (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) (hTIE2) (p140 TEK)AltName: CD_antigen=CD202b;Receptor protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Protein-tyrosine kinase (ambiguous)
Protein tyrosine kinase (ambiguous)
Receptor protein tyrosine kinase
TEK
TIE
TIE2
SynonymsNone
RefSeqNP_000450.2 (Protein)
NM_000459.3 (DNA/RNA sequence)
PfamPF00041 (fn3)
PF10430 (Ig_Tie2_1)
PF07714 (Pkinase_Tyr)
[Graphical view]


UniProtKB:Accession NumberQ02763
Entry nameTIE2_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitHomodimer. 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 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. Interacts (tyrosine phosphorylated) with TNIP2. Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain).
Subcellular locationCell 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.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00585C00008C01167
CompoundMgATP[protein]-L-tyrosineADP[protein]-L-tyrosine phosphate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotidearomatic ring (only carbon atom),peptide/proteinamine group,nucleotidearomatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI18420
15422

16761

PubChem888
5957

6022

             
2gy5A01UnboundUnboundUnboundUnboundUnbound
2gy7B01UnboundUnboundUnboundUnboundUnbound
2gy5A02UnboundUnboundUnboundUnboundUnbound
2gy7B02UnboundUnboundUnboundUnboundUnbound
2gy5A03UnboundUnboundUnboundUnboundUnbound
2gy7B03UnboundUnboundUnboundUnboundUnbound
2gy5A04UnboundUnboundUnboundUnboundUnbound
2gy7B04UnboundUnboundUnboundUnboundUnbound
1fvrA01UnboundUnboundUnboundUnboundUnbound
1fvrB01UnboundUnboundUnboundUnboundUnbound
2oo8X01UnboundUnboundUnboundUnboundUnbound
2oscA01UnboundUnboundUnboundUnboundUnbound
2p4iA01UnboundUnboundUnboundUnboundUnbound
2p4iB01UnboundUnboundUnboundUnboundUnbound
2wqbA01UnboundUnboundUnboundUnboundUnbound
3l8pA01UnboundUnboundUnboundUnboundUnbound
1fvrA02UnboundUnboundUnboundUnboundUnbound
1fvrB02UnboundUnboundUnboundUnboundUnbound
2oo8X02UnboundUnboundUnboundUnboundUnbound
2oscA02UnboundUnboundUnboundUnboundUnbound
2p4iA02UnboundUnboundUnboundUnboundUnbound
2p4iB02UnboundUnboundUnboundUnboundUnbound
2wqbA02UnboundUnboundUnboundUnboundUnbound
3l8pA02UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Literature [1], Swiss-prot;Q02763
pdbCatalytic residuesCofactor-binding residuescomment
           
2gy5A01               
 
 
2gy7B01               
 
 
2gy5A02               
 
 
2gy7B02               
 
 
2gy5A03               
 
 
2gy7B03               
 
 
2gy5A04               
 
 
2gy7B04               
 
 
1fvrA01               
 
invisible 861-866
1fvrB01               
 
invisible 861-866
2oo8X01               
 
invisible 844-848, 861-862, 895-898
2oscA01               
 
invisible 844-849, 859-862, 895-898
2p4iA01               
 
invisible 844-848, 857-870, 895-898
2p4iB01               
 
invisible 844-848, 860-862, 895-898
2wqbA01               
 
invisible 834-835, 860-872
3l8pA01               
 
invisible 858-868
1fvrA02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 996-999
1fvrB02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 996-998
2oo8X02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 986-996
2oscA02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 986-996
2p4iA02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 988-992
2p4iB02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 986-997
2wqbA02       ;ARG 968
ASN 969;ASP 982 (Magnesium binding)
mutant D964N, invisible 997
3l8pA02ASP 964;ARG 968
ASN 969;ASP 982 (Magnesium binding)
invisible 996-1000

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Figure 3
[3]FIG. 1
[5]Figure 12

references
[1]
CommentsX-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 808-1124, ACTIVE SITE, ATP-BINDING REGION.
PubMed ID11080633
JournalStructure
Year2000
Volume8
Pages1105-13
AuthorsShewchuk LM, Hassell AM, Ellis B, Holmes WD, Davis R, Horne EL, Kadwell SH, McKee DD, Moore JT
TitleStructure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.
Related PDB1fvr
Related UniProtKBQ02763
[2]
PubMed ID11513602
JournalBiochemistry
Year2001
Volume40
Pages10243-53
AuthorsMurray BW, Padrique ES, Pinko C, McTigue MA
TitleMechanistic effects of autophosphorylation on receptor tyrosine kinase catalysis: enzymatic characterization of Tie2 and phospho-Tie2.
[3]
PubMed ID12082108
JournalJ Biol Chem
Year2002
Volume277
Pages31768-73
AuthorsNiu XL, Peters KG, Kontos CD
TitleDeletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.
[4]
PubMed ID12469114
JournalNat Struct Biol
Year2003
Volume10
Pages38-44
AuthorsDavis S, Papadopoulos N, Aldrich TH, Maisonpierre PC, Huang T, Kovac L, Xu A, Leidich R, Radziejewska E, Rafique A, Goldberg J, Jain V, Bailey K, Karow M, Fandl J, Samuelsson SJ, Ioffe E, Rudge JS, Daly TJ, Radziejewski C, Yancopoulos GD
TitleAngiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering.
[5]
PubMed ID15350212
JournalMol Cell
Year2004
Volume15
Pages661-75
AuthorsNolen B, Taylor S, Ghosh G
TitleRegulation of protein kinases; controlling activity through activation segment conformation.
[6]
PubMed ID14749497
JournalRecent Prog Horm Res
Year2004
Volume59
Pages51-71
AuthorsPeters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, Dewhirst MW, Sankar
TitleFunctional significance of Tie2 signaling in the adult vasculature.
[7]
PubMed ID15769741
JournalJ Biol Chem
Year2005
Volume280
Pages20126-31
AuthorsKim KT, Choi HH, Steinmetz MO, Maco B, Kammerer RA, Ahn SY, Kim HZ, Lee GM, Koh GY
TitleOligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2.
[8]
PubMed ID16849318
JournalJ Biol Chem
Year2006
Volume281
Pages28408-14
AuthorsMacdonald PR, Progias P, Ciani B, Patel S, Mayer U, Steinmetz MO, Kammerer RA
TitleStructure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope.
[9]
CommentsX-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 23-445 ALONE AND IN COMPLEX WITH ANGPT2, GLYCOSYLATION AT ASN-140, DISUFIDE BONDS.
PubMed ID16732286
JournalNat Struct Mol Biol
Year2006
Volume13
Pages524-32
AuthorsBarton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB
TitleCrystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.
Related PDB2gy5,2gy7
Related UniProtKBQ02763
[10]
PubMed ID17350837
JournalBioorg Med Chem Lett
Year2007
Volume17
Pages2886-9
AuthorsHodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Caenepeel S, Cee VJ, Chaffee SC, Emery M, Fretland J, Gallant P, Gu Y, Johnson RE, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Wang L, Zhao H
TitleSynthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
Related PDB2oo8,2osc
Related UniProtKBQ02763
[11]
PubMed ID17253678
JournalJ Med Chem
Year2007
Volume50
Pages611-26
AuthorsHodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H
TitleEvolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
Related PDB2p4i
Related UniProtKBQ02763
[12]
PubMed ID19854647
JournalBioorg Med Chem Lett
Year2009
Volume19
Pages6670-4
AuthorsLuke RW, Ballard P, Buttar D, Campbell L, Curwen J, Emery SC, Griffen AM, Hassall L, Hayter BR, Jones CD, McCoull W, Mellor M, Swain ML, Tucker JA
TitleNovel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.
Related PDB2wqb
Related UniProtKBQ02763
[13]
PubMed ID20602996
JournalCell
Year2010
Volume141
Pages1117-34
AuthorsLemmon MA, Schlessinger J
TitleCell signaling by receptor tyrosine kinases.
[14]
PubMed ID19922791
JournalCell Signal
Year2010
Volume22
Pages527-32
AuthorsHansen TM, Singh H, Tahir TA, Brindle NP
TitleEffects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface.
[15]
PubMed ID20026268
JournalCell Signal
Year2010
Volume22
Pages676-83
AuthorsSturk C, Kim H, Jones N, Dumont DJ
TitleA negative regulatory role for Y1111 on the Tie-2 RTK.
[16]
PubMed ID20227369
JournalMol Cell
Year2010
Volume37
Pages643-55
AuthorsSeegar TC, Eller B, Tzvetkova-Robev D, Kolev MV, Henderson SC, Nikolov DB, Barton WA
TitleTie1-Tie2 interactions mediate functional differences between angiopoietin ligands.

comments
This enzyme is type 1 transmembrane protein receptor tyrosine kinase. This enzyme consists of the N-terminal extracellular region, the transmembrane region, and the C-terminal intracellular region (see [6]). The extracellular region is composed of two N-terminal Ig-like domains (CATH; 2.60.40.10), three epidermal growth factor (EGF) repeats (CATH; 2.170.300.10 or three 2.10.25.10), another Ig-like domain, and three fibronectin type III (FN3) (CATH; 2.60.40.10) repeats (see [8]). The intracellular region is composed of a juxtamembrane domain, a kinase domain, and a tail region.
The catalytic domain of this enzyme is homologous to that of vascular endothelial growth factor receptor (M00131 in EzCatDB).
This enzyme is essential in angiogenesis, along with its ligand proteins, angiopoietins (angiopoietin-1, angiopoietin-2, angiopoietin-3, and angiopoietin-4). This enzyme interacts with all the four angiopoietins.
According to the literature [9], the second Ig-domain of the extracellular region of this enzyme interacts with fibrinogen-like region of angiopoietin-2 (see PDB;2gy7). Binding of the multimeric angiopoietins to this enzyme may cluster the receptor, bringing into close proximity its kinase domains, which can phosphorylate each other, resulting in receptor activation and initiation of downstream signaling (see [9]).
The C-terminal tail of the intracellular region negatively regulates receptor autophosphorylation and kinase activity (see [1] and [13]).

createdupdated
2011-10-192012-12-27


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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