TEK (TEK tyrosine kinase, endothelial)

2012-04-01   Mohammad B Hossain , Nahir Cortes-Santiago , Dan Liu , Vanesa Martin , Candelaria Gomez-Manzano 

Identity

HGNC
LOCATION
9p21.2
LOCUSID
ALIAS
CD202B,GLC3E,TIE-2,TIE2,VMCM,VMCM1
FUSION GENES

DNA/RNA

Atlas Image
Schematic representation of TEK gene, coding region and protein. UTR, untranslated region; Ig, immunoglobulin; EGF, epithelial growth factor.

Description

Tie2 DNA contains 121025 bp, which has 23 coding exons, in plus strand.

Transcription

mRNA contains 4817 bp transcribed in centromeric to telomeric orientation; 2 other transcripture structures by alternative splicing have been predicted. The mRNA contains a long (442 bp) 5-UTR with 5 upstream ORFs and 1 IRES that allows the RNA to be translated under hypoxic conditions.

Proteins

Description

Tie2 contains 1124 amino acids and belongs to the protein kinase superfamily, Tyr protein kinase family, Tie subfamily. Tie2 receptor contains three epidermal growth factor (EGF)-like domains flanked by three Ig-like (immunoglobulin-like) domains, followed by three fibronectin type-III domains in the extracellular domain. Tie2 possesses one intracellular split tyrosine kinase domain, which is highly conserved between the Tie members sharing a 76% sequence homology. It also contains a single transmembrane domain.
Atlas Image

Expression

TEK/Tie2 is predominantly expressed by vascular endothelial cells: It is detectable in the critical process of new vessels formation during early development, and in the adult in response to cyclic hormonal stimulation in the ovary and uterus, as well as in healing skin wounds. High levels of expression of TEK are found in placenta, lung, spleen, and heart tissues. Hematopoietic stem cells, progenitor and mature pericytes, neural progenitor cells, and a subpopulation of monocytes (Tie2-expressing monocytes) also express Tie2/TEK. In addition, its expression might be induced in response to other pathological conditions as described bellow.

Localisation

Cell membrane.

Function

TEK/Tie2 is a tyrosine-kinase transmembrane receptor involved in signaling pathways upon stimuli by angiopoietins (natural ligands). It guides the proper patterning of endothelial cells during blood vessel formation and also plays role in vessel remodeling, cell survival, cell migration, and cell-to-matrix and cell-to-cell adhesion. TEK/Tie2 signaling pathway is also involved in Toll-like receptor 2 and integrin signaling.

Homology

H. sapiens: TEK;
P. troglodytes: TEK;
B. Taurus: TEK;
M. musculus: Tek;
D. rerio: tie2;
R. novergicus: Tek;
G. gallus: TEK.

Mutations

Germinal

Heterozygous TEK substitutions: R849W (10 of 17 families with hereditary mucocutaneous venous malformation, VMCM), Y897S, Y897C, R915H, R918C, V1919L, A925C, K1100N. These mutations result in in vitro ligand-independent hyperphosphorylation.

Somatic

Several somatic mutations have been identified related to non-inherited vascular anomalies:
1) del-Tie2 mutant, consists in an in-frame deletion of 129bp, corresponding to a loss of exon 3 and part of exon 4 (amino acid 122-165 of extracellular Ig-like ligand-binding domain, 43 aa deletion in Ig-like domain);
2) Mutations in exon 17 of TEK/Tie2 in 49,1% (28 of 57 individuals): two somatic TEK mutations (Y897C, R915C) in vascular tumors, and seven somatic TEK mutations in vascular malformations (Y897H, Y897C, L914F, R915C, S917I, R918C, R918H).
In patients with human intramuscular haemangioma, the following Tie2 mutations have been described: G833D, Q837H.

Implicated in

Entity name
Various cancers
Note
Cancer: acute myeloid leukemia and chronic myelogenous leukemia, and solid tumors, such as malignant gliomas, breast cancer, thyroid cancer, gastric cancer, bladder cancer, endometrial carcinoma.
Present in both the vasculature and cancer cells of several solid tumors.
Disease
Overexpressed in the vasculature of several tumors, as breast cancer, non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, Kaposis sarcoma, and astrocytoma.
Overexpressed in the cancer cells -outside of the vascular compartment- in Acute and Chronic Myeloid Leukemia, and solid tumors, such as Malignant Astrocytomas, Breast Cancer, Thyroid Cancer, Gastric Cancer, Endometrial Adenocarcinoma.
Overexpressed in brain tumor stem cells and leukemic blasts.
Prognosis
Correlation of TEK/Tie2 expression and malignancy in Gliomas. Tie2 activation results in increased levels of expression of ABC transporter, and eventually chemoresistance of malignant gliomas. Tie2 regulates migration and invasion of these tumors.
Cellular Tie2 and soluble Tie2 expression might be associated to a higher risk of metastasis in patients with breast and bladder cancer, respectively.
Entity name
Sporadic and inherited forms of mucocutaneous venous malformations (VMCM) and intramuscular haemangioma
Disease
Venous malformations are vascular masses composed of dilated channels lined by endothelial cells, with a reduced coverage by pericytes, leading to functionally low resistance vessels. See Mutation section for description of TEK/Tie2 mutations related with these diseases. Some of these mutations affect TEK/Tie2 activity and/or response to ligand.
Prognosis
Not determined.
Entity name
Systemic sclerosis: microangiopathies
Disease
Systemic sclerosis (SSc) is an autoimmune disease characterized by altered angiogenesis that precede fibrosis of skin and internal organs. The abnormal angiogenesis is one of the major causes of microangiopathies.
Prognosis
Report suggesting that soluble Tie2 in serum samples from patients with systemic sclerosis is related to the development of vascular abnormalities of this disease (nailfold bleeding and pulmonary arterial hypertension).
Cytogenetics
Not determined.
Entity name
Wide range of diseases with a vascular and/or inflammatory component, such as psoriasis, pulmonary hypertension, rheumatoid arthritis
Disease
Psoriatic lesions are characterized by elongation and dilatation of papillary dermis. Tie2 transgenic mice showed epidermal hyperproliferation, inflammatory cell accumulation, and altered dermal angiogenesis, mimicking the phenotype present in human psoriasis.
Pulmonary hypertension is characterized by high pulmonary arterial pressure. Increased levels of activated TEK/Tie2 and Angiopoietin1 have been reported.
Rheumatoid arthritis is characterized by chronic inflammatory changes in synovial tissue and pathological angiogenesis. Tie2 has been shown to be upregulated in synovial tissue of patients with rheumatoid arthritis and to mediate pathological angiogenesis and invasion within affected synovial tissue.
Prognosis
Not determined.
Cytogenetics
Not determined.
Entity name
Cerebrovascular disease: stroke
Disease
In stroke, arterial occlusion of one or more arteries in the brain leads to focal or global ischemia and tissue damage and eventual death. Expression of activated Tie2 and Ang1 lead to enhanced neovascularization, vessel stabilization and improved recovery.
Prognosis
Reports suggest that activation of Tie2-mediated pathway is essential in initiation of survival responses in neural progenitor cells against cerebral ischemia and hypoxia.
Cytogenetics
Not determined.

Bibliography

Pubmed IDLast YearTitleAuthors
152609862004Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.Arai F et al
194091992009An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation.Bai Y et al
185440442009Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke.Chen J et al
187117492009Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke.Cui X et al
161694662005Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.De Palma M et al
131304652003Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis.DeBusk LM et al
125712572003Signaling molecules in nonfamilial pulmonary hypertension.Du L et al
162258622006Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling.Eklund L et al
112837232001Tie receptors: new modulators of angiogenic and lymphangiogenic responses.Jones N et al
218499062011Do serum angiopoietin-1, angiopoietin-2, and their receptor Tie-2 and 4G/5G variant of PAI-1 gene have a role in the pathogenesis of preeclampsia?Kamal M et al
113484592001Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis.Kuroda K et al
171893822006Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix.Lee OH et al
190792592009Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.Limaye N et al
213213792010Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype.Liu D et al
157183072005Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival.Loges S et al
168493182006Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope.Macdonald PR et al
183660152008Tie2: a journey from normal angiogenesis to cancer and beyond.Martin V et al
194211502009Tie2-mediated multidrug resistance in malignant gliomas is associated with upregulation of ABC transporters.Martin V et al
157539922005Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma.Meunier-Carpentier S et al
119162922002Tie-2 and angiopoietin-1 expression in human thyroid tumors.Mitsutake N et al
117554662002Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia.Müller A et al
213667132011Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis.Noda S et al
164578192006The Tie2 5' untranslated region is inhibitory to 5' end-mediated translation initiation.Park EH et al
94591451998Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.Peters KG et al
218581612011Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis.Saber T et al
184251192008Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.Saharinen P et al
172956462007Angiogenic factors in normal endometrium and endometrial adenocarcinoma.Saito M et al
169568192006Expression of angiopoietins and their receptor Tie2 in the bone marrow of patients with acute myeloid leukemia.Schliemann C et al
120105712002Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue.Shahrara S et al
110806332000Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.Shewchuk LM et al
119924022002Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer.Shirakawa K et al
188072122009Serum levels of angiogenic factors and their prognostic relevance in bladder cancer.Szarvas T et al
149915312004Autocrine/paracrine role of the angiopoietin-1 and -2/Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid arthritis.Takahara K et al
89802251996Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.Vikkula M et al
153779982004Transformation of vascular endothelial cells by a point mutation in the Tie2 gene from human intramuscular haemangioma.Wang H et al
161856652005Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer.Wang J et al
219629232011Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations.Ye C et al
147422532004Targeting the Tie2/Tek receptor in astrocytomas.Zadeh G et al

Other Information

Locus ID:

NCBI: 7010
MIM: 600221
HGNC: 11724
Ensembl: ENSG00000120156

Variants:

dbSNP: 7010
ClinVar: 7010
TCGA: ENSG00000120156
COSMIC: TEK

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000120156ENST00000380036Q02763
ENSG00000120156ENST00000406359Q02763
ENSG00000120156ENST00000519080E5RIV9
ENSG00000120156ENST00000519097Q02763
ENSG00000120156ENST00000615002B5A954

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
HIF-1 signaling pathwayKEGGhsa04066
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
HemostasisREACTOMER-HSA-109582
Cell surface interactions at the vascular wallREACTOMER-HSA-202733
Tie2 SignalingREACTOMER-HSA-210993
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
184251192008Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.159
173274112007Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer.147
225855762012Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling.140
262695152015Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.138
184251202008Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1.133
185198262008Molecular genetics of successful smoking cessation: convergent genome-wide association study results.130
192234732009Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.117
175137912007Expression of Tie-2 by human monocytes and their responses to angiopoietin-2.97
190792592009Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.81
190792592009Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.81

Citation

Mohammad B Hossain ; Nahir Cortes-Santiago ; Dan Liu ; Vanesa Martin ; Candelaria Gomez-Manzano

TEK (TEK tyrosine kinase, endothelial)

Atlas Genet Cytogenet Oncol Haematol. 2012-04-01

Online version: http://atlasgeneticsoncology.org/gene/42517/tek

Historical Card

2009-01-01 TEK (TEK tyrosine kinase, endothelial) by  Dan Liu,Vanesa Martin,Candelaria Gomez-Manzano 

Department Neuro-Oncology, Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA