DB code: M00325

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 2.60.40.10 : Immunoglobulin-like
2.60.40.10 : Immunoglobulin-like
2.170.300.10 :
2.60.40.10 : Immunoglobulin-like
2.60.40.10 : Immunoglobulin-like
2.60.40.10 : Immunoglobulin-like
2.60.40.10 : Immunoglobulin-like
-.-.-.- :
-.-.-.- :
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
-.-.-.- :
E.C. 2.7.10.1
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 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-like M00131 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 1 M00125 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

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q02763 Angiopoietin-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;
None NP_000450.2 (Protein)
NM_000459.3 (DNA/RNA sequence)
PF00041 (fn3)
PF10430 (Ig_Tie2_1)
PF07714 (Pkinase_Tyr)
[Graphical View]

KEGG enzyme name
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

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q02763 TIE2_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. 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 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). 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.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00585 C00008 C01167
E.C.
Compound Mg ATP [protein]-L-tyrosine ADP [protein]-L-tyrosine phosphate
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide aromatic ring (only carbon atom),peptide/protein amine group,nucleotide aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI 18420
 18420
 		15422
 15422
 		16761
 16761
PubChem 888
 888
 		5957
 5957
 		6022
 6022
2gy5A01 Unbound Unbound Unbound Unbound Unbound
2gy7B01 Unbound Unbound Unbound Unbound Unbound
2gy5A02 Unbound Unbound Unbound Unbound Unbound
2gy7B02 Unbound Unbound Unbound Unbound Unbound
2gy5A03 Unbound Unbound Unbound Unbound Unbound
2gy7B03 Unbound Unbound Unbound Unbound Unbound
2gy5A04 Unbound Unbound Unbound Unbound Unbound
2gy7B04 Unbound Unbound Unbound Unbound Unbound
1fvrA01 Unbound Unbound Unbound Unbound Unbound
1fvrB01 Unbound Unbound Unbound Unbound Unbound
2oo8X01 Unbound Unbound Unbound Unbound Unbound
2oscA01 Unbound Unbound Unbound Unbound Unbound
2p4iA01 Unbound Unbound Unbound Unbound Unbound
2p4iB01 Unbound Unbound Unbound Unbound Unbound
2wqbA01 Unbound Unbound Unbound Unbound Unbound
3l8pA01 Unbound Unbound Unbound Unbound Unbound
1fvrA02 Unbound Unbound Unbound Unbound Unbound
1fvrB02 Unbound Unbound Unbound Unbound Unbound
2oo8X02 Unbound Unbound Unbound Unbound Unbound
2oscA02 Unbound Unbound Unbound Unbound Unbound
2p4iA02 Unbound Unbound Unbound Unbound Unbound
2p4iB02 Unbound Unbound Unbound Unbound Unbound
2wqbA02 Unbound Unbound Unbound Unbound Unbound
3l8pA02 Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [1], Swiss-prot;Q02763

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
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
1fvrA02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 996-999
1fvrB02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 996-998
2oo8X02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 986-996
2oscA02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 986-996
2p4iA02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 988-992
2p4iB02 ASP 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
3l8pA02 ASP 964;ARG 968 ASN 969;ASP 982 (Magnesium binding) invisible 996-1000

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Figure 3
[3]
FIG. 1
[5]
Figure 12

References
[1]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 808-1124, ACTIVE SITE, ATP-BINDING REGION.
Medline ID
PubMed ID 11080633
Journal Structure
Year 2000
Volume 8
Pages 1105-13
Authors Shewchuk LM, Hassell AM, Ellis B, Holmes WD, Davis R, Horne EL, Kadwell SH, McKee DD, Moore JT
Title Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.
Related PDB 1fvr
Related UniProtKB Q02763
[2]
Resource
Comments
Medline ID
PubMed ID 11513602
Journal Biochemistry
Year 2001
Volume 40
Pages 10243-53
Authors Murray BW, Padrique ES, Pinko C, McTigue MA
Title Mechanistic effects of autophosphorylation on receptor tyrosine kinase catalysis: enzymatic characterization of Tie2 and phospho-Tie2.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 12082108
Journal J Biol Chem
Year 2002
Volume 277
Pages 31768-73
Authors Niu XL, Peters KG, Kontos CD
Title Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function. Evidence for an autoinhibitory mechanism.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 12469114
Journal Nat Struct Biol
Year 2003
Volume 10
Pages 38-44
Authors Davis 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
Title Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 15350212
Journal Mol Cell
Year 2004
Volume 15
Pages 661-75
Authors Nolen B, Taylor S, Ghosh G
Title Regulation of protein kinases; controlling activity through activation segment conformation.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 14749497
Journal Recent Prog Horm Res
Year 2004
Volume 59
Pages 51-71
Authors Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, Dewhirst MW, Sankar
Title Functional significance of Tie2 signaling in the adult vasculature.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 15769741
Journal J Biol Chem
Year 2005
Volume 280
Pages 20126-31
Authors Kim KT, Choi HH, Steinmetz MO, Maco B, Kammerer RA, Ahn SY, Kim HZ, Lee GM, Koh GY
Title Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 16849318
Journal J Biol Chem
Year 2006
Volume 281
Pages 28408-14
Authors Macdonald PR, Progias P, Ciani B, Patel S, Mayer U, Steinmetz MO, Kammerer RA
Title Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope.
Related PDB
Related UniProtKB
[9]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 23-445 ALONE AND IN COMPLEX WITH ANGPT2, GLYCOSYLATION AT ASN-140, DISUFIDE BONDS.
Medline ID
PubMed ID 16732286
Journal Nat Struct Mol Biol
Year 2006
Volume 13
Pages 524-32
Authors Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB
Title Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.
Related PDB 2gy5 2gy7
Related UniProtKB Q02763
[10]
Resource
Comments
Medline ID
PubMed ID 17350837
Journal Bioorg Med Chem Lett
Year 2007
Volume 17
Pages 2886-9
Authors Hodous 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
Title Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
Related PDB 2oo8 2osc
Related UniProtKB Q02763
[11]
Resource
Comments
Medline ID
PubMed ID 17253678
Journal J Med Chem
Year 2007
Volume 50
Pages 611-26
Authors Hodous 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
Title Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
Related PDB 2p4i
Related UniProtKB Q02763
[12]
Resource
Comments
Medline ID
PubMed ID 19854647
Journal Bioorg Med Chem Lett
Year 2009
Volume 19
Pages 6670-4
Authors Luke 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
Title Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.
Related PDB 2wqb
Related UniProtKB Q02763
[13]
Resource
Comments
Medline ID
PubMed ID 20602996
Journal Cell
Year 2010
Volume 141
Pages 1117-34
Authors Lemmon MA, Schlessinger J
Title Cell signaling by receptor tyrosine kinases.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 19922791
Journal Cell Signal
Year 2010
Volume 22
Pages 527-32
Authors Hansen TM, Singh H, Tahir TA, Brindle NP
Title Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 20026268
Journal Cell Signal
Year 2010
Volume 22
Pages 676-83
Authors Sturk C, Kim H, Jones N, Dumont DJ
Title A negative regulatory role for Y1111 on the Tie-2 RTK.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 20227369
Journal Mol Cell
Year 2010
Volume 37
Pages 643-55
Authors Seegar TC, Eller B, Tzvetkova-Robev D, Kolev MV, Henderson SC, Nikolov DB, Barton WA
Title Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands.
Related PDB
Related UniProtKB

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]).

Created Updated
2011-10-19 2012-12-27