TIE2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: TIE2_HUMAN
• UniProt AC: Q02763
• Protein Name: Angiopoietin-1 receptor
• Gene Name: TEK
• Organism: Homo sapiens (Human).
• Sequence Length: 1124
• Subcellular Localization: Cell membrane ; Single-pass type I membrane protein. Cell junction . Cell junction, focal adhesion . Cytoplasm, cytoskeleton. Secreted . Recruited to cell-cell contacts in quiescent endothelial cells (PubMed:18425120, PubMed:18425119). Colocalizes wi
• Protein Description: 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..
• Protein Sequence: MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRDFEALMNQHQDPLEVTQDVTREWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQQASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGSFIHSVPRHEVPDILEVHLPHAQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGECICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNEACHPGFYGPDCKLRCSCNNGEMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIEVNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNHTDHFSVAIFTIHRILPPDSGVWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKKLLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTASIGLPPPRGLNLLPKSQTTLNLTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSVLLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPPQPENIKISNITHSSAVISWTILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGSSNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSAEEAA

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
115	Phosphorylation	GEAIRIRTMKMRQQA CCEEHHEEEHHHHCC	20.83	-
130	Phosphorylation	SFLPATLTMTVDKGD CCCCEEEEEEEECCC	13.36	22210691
140	N-linked_Glycosylation	VDKGDNVNISFKKVL EECCCCEEEEEEEEE	30.37	16732286
142	Phosphorylation	KGDNVNISFKKVLIK CCCCEEEEEEEEEEC	26.30	24719451
158	N-linked_Glycosylation	EDAVIYKNGSFIHSV CCEEEEECCCEEEEC	34.08	UniProtKB CARBOHYD
164	Phosphorylation	KNGSFIHSVPRHEVP ECCCEEEECCCCCCC	29.06	-
399	N-linked_Glycosylation	VLHPKDFNHTDHFSV EECCCCCCCCCCCEE	47.48	UniProtKB CARBOHYD
438	N-linked_Glycosylation	GMVEKPFNISVKVLP EECCCCCEEEEEECC	33.87	UniProtKB CARBOHYD
464	N-linked_Glycosylation	GHNFAVINISSEPYF CCCEEEEEECCCCCC	22.84	UniProtKB CARBOHYD
560	N-linked_Glycosylation	PKSQTTLNLTWQPIF CCCCCEEEEEEEECC	33.08	UniProtKB CARBOHYD
596	N-linked_Glycosylation	QNIKVPGNLTSVLLN CCCCCCCCHHHHHHC	33.79	19159218
649	N-linked_Glycosylation	PENIKISNITHSSAV CCCCEEEECCCCCCE	46.80	UniProtKB CARBOHYD
652 (in isoform 3)	Phosphorylation	-	18.89	30153514
691	N-linked_Glycosylation	HVDVKIKNATITQYQ CEEEEEECCEEEEEE	45.87	UniProtKB CARBOHYD
693	Phosphorylation	DVKIKNATITQYQLK EEEEECCEEEEEEEC	33.67	24702127
695	Phosphorylation	KIKNATITQYQLKGL EEECCEEEEEEECCC	19.50	24702127
697	Phosphorylation	KNATITQYQLKGLEP ECCEEEEEEECCCCC	13.73	24702127
816	Phosphorylation	NNPDPTIYPVLDWND CCCCCCEECCCCHHH	6.97	-
860	Phosphorylation	AIKRMKEYASKDDHR HHHHHHHHCCCCCCC	15.62	11513602
897	Phosphorylation	GACEHRGYLYLAIEY HHHCCCCEEEEEEEE	7.67	11080633
899	Phosphorylation	CEHRGYLYLAIEYAP HCCCCEEEEEEEECC	5.89	-
976	Phosphorylation	NILVGENYVAKIADF CCCCCCCHHHHHHHH	9.47	-
992	Phosphorylation	LSRGQEVYVKKTMGR CCCCCEEEEEECCCC	13.05	8382358
996	Phosphorylation	QEVYVKKTMGRLPVR CEEEEEECCCCCCCE	21.09	-
1048	Phosphorylation	GMTCAELYEKLPQGY CCCHHHHHHHCCCCC	11.52	11080633
1102	Phosphorylation	MLEERKTYVNTTLYE HHHHHCHHCCCCHHH	8.50	20973951
1108	Phosphorylation	TYVNTTLYEKFTYAG HHCCCCHHHHCEECC	18.25	12665569
1113	Phosphorylation	TLYEKFTYAGIDCSA CHHHHCEECCCCCCH	13.13	14665640
1119	Phosphorylation	TYAGIDCSAEEAA-- EECCCCCCHHHCC--	34.66	23403867

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
860	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
992	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
1048	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
1102	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
1108	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
1113	Y	Phosphorylation	Kinase	TEK	Q02763	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	CBL	P22681	PMID:23754070

Functions of PTM Sites

Oops, there are no descriptions of PTM sites of TIE2_HUMAN !!

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
596	N-linked Glycosylation	600 (4)	V ⇒ L	rs35030851	Blood protein levels	28240269

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
ANGP1_HUMAN	ANGPT1	physical	12427764
ANGP2_HUMAN	ANGPT2	physical	12427764
ANGP1_HUMAN	ANGPT1	physical	8980223
ANGP4_HUMAN	ANGPT4	physical	10051567
ANGP1_HUMAN	ANGPT1	physical	9723709
ANGP2_HUMAN	ANGPT2	physical	9723709
ANGP1_HUMAN	ANGPT1	physical	9204896
ANGP2_HUMAN	ANGPT2	physical	9204896
TNIP2_HUMAN	TNIP2	physical	12609966
A4_HUMAN	APP	physical	21832049
PTN11_HUMAN	PTPN11	physical	28065597
PTPRR_HUMAN	PTPRR	physical	28065597
FAK1_HUMAN	PTK2	physical	25792870
AKT1_HUMAN	AKT1	physical	25792870
ILKAP_HUMAN	ILKAP	physical	28065597
DUS18_HUMAN	DUSP18	physical	28065597
STYX_HUMAN	STYX	physical	28065597
TIE2_HUMAN	TEK	physical	26285778

Drug and Disease Associations

• Kegg Disease
• H00531: Venous malformations, including: Sporadic venous malformation; Cutaneomucosal venous malformation; G
• OMIM Disease
• 600195: Dominantly inherited venous malformations (VMCM)
• Kegg Drug
• D10334: Rebastinib (USAN)
• D10399: Rebastinib Tosylate (USAN)
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

N-linked Glycosylation

"Crystal structures of the Tie2 receptor ectodomain and theangiopoietin-2-Tie2 complex.";
Barton W.A., Tzvetkova-Robev D., Miranda E.P., Kolev M.V.,Rajashankar K.R., Himanen J.P., Nikolov D.B.;
Nat. Struct. Mol. Biol. 13:524-532(2006).
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 23-445 ALONE AND IN COMPLEXWITH ANGPT2, GLYCOSYLATION AT ASN-140, AND DISULFIDE BONDS.
PubMed: 16732286

"Glycoproteomics analysis of human liver tissue by combination ofmultiple enzyme digestion and hydrazide chemistry.";
Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
J. Proteome Res. 8:651-661(2009).
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-596, AND MASSSPECTROMETRY.
PubMed: 19159218

Phosphorylation

"Adaptor ShcA protein binds tyrosine kinase Tie2 receptor andregulates migration and sprouting but not survival of endothelialcells.";
Audero E., Cascone I., Maniero F., Napione L., Arese M.,Lanfrancone L., Bussolino F.;
J. Biol. Chem. 279:13224-13233(2004).
Cited for: FUNCTION AS ANGPT1 RECEPTOR IN PHOSPHORYLATION OF SHC1 AND PIK3R1;REGULATION OF CELL MIGRATION AND ANGIOGENESIS, AUTOPHOSPHORYLATION,MUTAGENESIS OF TYR-1102, PHOSPHORYLATION AT TYR-1102, CATALYTICACTIVITY, AND INTERACTION WITH SHC1.
PubMed: 14665640

"Mechanistic effects of autophosphorylation on receptor tyrosinekinase catalysis: enzymatic characterization of Tie2 and phospho-Tie2.";
Murray B.W., Padrique E.S., Pinko C., McTigue M.A.;
Biochemistry 40:10243-10253(2001).
Cited for: CATALYTIC ACTIVITY, ENZYME REGULATION, MASS SPECTROMETRY, ANDPHOSPHORYLATION AT TYR-860; TYR-992 AND TYR-1108.
PubMed: 11513602