TEK (TEK tyrosine kinase, endothelial)

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

Identity

HGNC

TEK

LOCATION

9p21.2

LOCUSID

7010

ALIAS

CD202B,GLC3E,TIE-2,TIE2,VMCM,VMCM1

FUSION GENES

Show Gene Fusions

DNA/RNA

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.

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
15260986	2004	Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.	Arai F et al
19409199	2009	An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation.	Bai Y et al
18544044	2009	Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke.	Chen J et al
18711749	2009	Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke.	Cui X et al
16169466	2005	Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.	De Palma M et al
13130465	2003	Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis.	DeBusk LM et al
12571257	2003	Signaling molecules in nonfamilial pulmonary hypertension.	Du L et al
16225862	2006	Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling.	Eklund L et al
11283723	2001	Tie receptors: new modulators of angiogenic and lymphangiogenic responses.	Jones N et al
21849906	2011	Do 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
11348459	2001	Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis.	Kuroda K et al
17189382	2006	Expression 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
19079259	2009	Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.	Limaye N et al
21321379	2010	Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype.	Liu D et al
15718307	2005	Analysis 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
16849318	2006	Structure of the extracellular domain of Tie receptor tyrosine kinases and localization of the angiopoietin-binding epitope.	Macdonald PR et al
18366015	2008	Tie2: a journey from normal angiogenesis to cancer and beyond.	Martin V et al
19421150	2009	Tie2-mediated multidrug resistance in malignant gliomas is associated with upregulation of ABC transporters.	Martin V et al
15753992	2005	Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma.	Meunier-Carpentier S et al
11916292	2002	Tie-2 and angiopoietin-1 expression in human thyroid tumors.	Mitsutake N et al
11755466	2002	Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia.	Müller A et al
21366713	2011	Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis.	Noda S et al
16457819	2006	The Tie2 5' untranslated region is inhibitory to 5' end-mediated translation initiation.	Park EH et al
9459145	1998	Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis.	Peters KG et al
21858161	2011	Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis.	Saber T et al
18425119	2008	Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.	Saharinen P et al
17295646	2007	Angiogenic factors in normal endometrium and endometrial adenocarcinoma.	Saito M et al
16956819	2006	Expression of angiopoietins and their receptor Tie2 in the bone marrow of patients with acute myeloid leukemia.	Schliemann C et al
12010571	2002	Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue.	Shahrara S et al
11080633	2000	Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.	Shewchuk LM et al
11992402	2002	Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer.	Shirakawa K et al
18807212	2009	Serum levels of angiogenic factors and their prognostic relevance in bladder cancer.	Szarvas T et al
14991531	2004	Autocrine/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
8980225	1996	Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.	Vikkula M et al
15377998	2004	Transformation of vascular endothelial cells by a point mutation in the Tie2 gene from human intramuscular haemangioma.	Wang H et al
16185665	2005	Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer.	Wang J et al
21962923	2011	Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations.	Ye C et al
14742253	2004	Targeting 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 ID	Transcript ID	Uniprot
ENSG00000120156	ENST00000380036	Q02763
ENSG00000120156	ENST00000406359	Q02763
ENSG00000120156	ENST00000519080	E5RIV9
ENSG00000120156	ENST00000519097	Q02763
ENSG00000120156	ENST00000615002	B5A954

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Rheumatoid arthritis	KEGG	ko05323
Rheumatoid arthritis	KEGG	hsa05323
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
HIF-1 signaling pathway	KEGG	hsa04066
Ras signaling pathway	KEGG	hsa04014
Rap1 signaling pathway	KEGG	hsa04015
Rap1 signaling pathway	KEGG	ko04015
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
RAF/MAP kinase cascade	REACTOME	R-HSA-5673001
Fc epsilon receptor (FCERI) signaling	REACTOME	R-HSA-2454202
FCERI mediated MAPK activation	REACTOME	R-HSA-2871796
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-2 signaling	REACTOME	R-HSA-451927
Interleukin receptor SHC signaling	REACTOME	R-HSA-912526
Interleukin-3, 5 and GM-CSF signaling	REACTOME	R-HSA-512988
Hemostasis	REACTOME	R-HSA-109582
Cell surface interactions at the vascular wall	REACTOME	R-HSA-202733
Tie2 Signaling	REACTOME	R-HSA-210993
Signal Transduction	REACTOME	R-HSA-162582
Signaling by EGFR	REACTOME	R-HSA-177929
GRB2 events in EGFR signaling	REACTOME	R-HSA-179812
SHC1 events in EGFR signaling	REACTOME	R-HSA-180336
Signaling by Insulin receptor	REACTOME	R-HSA-74752
Insulin receptor signalling cascade	REACTOME	R-HSA-74751
IRS-mediated signalling	REACTOME	R-HSA-112399
SOS-mediated signalling	REACTOME	R-HSA-112412
Signalling by NGF	REACTOME	R-HSA-166520
NGF signalling via TRKA from the plasma membrane	REACTOME	R-HSA-187037
Signalling to ERKs	REACTOME	R-HSA-187687
Signalling to RAS	REACTOME	R-HSA-167044
Signalling to p38 via RIT and RIN	REACTOME	R-HSA-187706
Prolonged ERK activation events	REACTOME	R-HSA-169893
Frs2-mediated activation	REACTOME	R-HSA-170968
ARMS-mediated activation	REACTOME	R-HSA-170984
Signaling by PDGF	REACTOME	R-HSA-186797
Downstream signal transduction	REACTOME	R-HSA-186763
Signaling by VEGF	REACTOME	R-HSA-194138
VEGFA-VEGFR2 Pathway	REACTOME	R-HSA-4420097
VEGFR2 mediated cell proliferation	REACTOME	R-HSA-5218921
Signaling by SCF-KIT	REACTOME	R-HSA-1433557
MAPK family signaling cascades	REACTOME	R-HSA-5683057
MAPK1/MAPK3 signaling	REACTOME	R-HSA-5684996
Signaling by GPCR	REACTOME	R-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	REACTOME	R-HSA-2404192
IGF1R signaling cascade	REACTOME	R-HSA-2428924
IRS-related events triggered by IGF1R	REACTOME	R-HSA-2428928
Signaling by Leptin	REACTOME	R-HSA-2586552
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
NCAM signaling for neurite out-growth	REACTOME	R-HSA-375165
RET signaling	REACTOME	R-HSA-8853659

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38195021	2024	TIE2 expression in hypertensive ICH and its therapeutic modulation with AKB-9778: Implications for brain vascular health.	0
38195021	2024	TIE2 expression in hypertensive ICH and its therapeutic modulation with AKB-9778: Implications for brain vascular health.	0
36876965	2023	Expression of Tie2 (angiopoietin receptor) on the monocyte subpopulations from ischemic stroke patients: Histological and flowcytometric studies.	0
36949696	2023	[Expression of Tyrosine Kinase Receptor 2 in Oral Squamous Cell Carcinoma and the Effect on Cell Proliferation and Migration and Epithelial-Mesenchymal Transition Process].	0
37005879	2023	Hsa_circ_0070661 inhibits cancer progression through miR-556-5p/TEK axis in lung adenocarcinoma.	1
37249455	2023	Polymorphisms in TIE2 and ANGPT-1 genes are associated with protection against diabetic retinopathy in a Brazilian population.	0
37658401	2023	Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.	0
37819742	2023	METTL3-Mediated RNA m6A Modification Regulates the Angiogenic Behaviors of Retinal Endothelial Cells by Methylating MMP2 and TIE2.	0
38162654	2023	Type I Interferons induce endothelial destabilization in Systemic Lupus Erythematosus in a Tie2-dependent manner.	0
36876965	2023	Expression of Tie2 (angiopoietin receptor) on the monocyte subpopulations from ischemic stroke patients: Histological and flowcytometric studies.	0
36949696	2023	[Expression of Tyrosine Kinase Receptor 2 in Oral Squamous Cell Carcinoma and the Effect on Cell Proliferation and Migration and Epithelial-Mesenchymal Transition Process].	0
37005879	2023	Hsa_circ_0070661 inhibits cancer progression through miR-556-5p/TEK axis in lung adenocarcinoma.	1
37249455	2023	Polymorphisms in TIE2 and ANGPT-1 genes are associated with protection against diabetic retinopathy in a Brazilian population.	0
37658401	2023	Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.	0
37819742	2023	METTL3-Mediated RNA m6A Modification Regulates the Angiogenic Behaviors of Retinal Endothelial Cells by Methylating MMP2 and TIE2.	0

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/tekid42517ch9p21

Historical Card

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

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