Alternative titles; symbols
HGNC Approved Gene Symbol: TEK
SNOMEDCT: 699301008;
Cytogenetic location: 9p21.2 Genomic coordinates (GRCh38): 9:27,109,141-27,230,178 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21.2 | Glaucoma 3, primary congenital, E | 617272 | Autosomal dominant | 3 |
| Venous malformations, multiple cutaneous and mucosal | 600195 | Autosomal dominant | 3 |
The TEK receptor tyrosine kinase is expressed almost exclusively in endothelial cells in mice, rats, and humans. This receptor possesses a unique extracellular domain containing 2 immunoglobulin-like loops separated by 3 epidermal growth factor-like repeats that are connected to 3 fibronectin type III-like repeats. The complex extracellular domain and the fact that the expression of this receptor tyrosine kinase is restricted to the endothelial cell lineage suggest that TEK plays a unique role within this cell lineage. In fact, disruption of the TEK gene by homologous recombination in ES cells results in embryonic lethality in homozygous mutant mouse embryos due to deficiency of the endothelium. The ligand for the receptor is angiopoietin-1 (ANG1; 601667).
The tek gene and its closely related subfamily member, tie, have both been mapped to mouse chromosome 4 (Dumont et al., 1992; Sato et al., 1993), and the human TIE gene has been localized to human 1p34-p33 by Partanen et al. (1992). By isotopic in situ hybridization, Dumont et al. (1994) assigned the human TEK gene to 9p21.
See TIE1 (600222) for discussion of the relationship between TEK (TIE2) and the TIE1 receptor tyrosine kinase in vascular development.
Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins ANG1 and ANG2 (601922) are angiogenic growth factors acting through TIE2. Ramsden et al. (2001) examined the expression and regulation of the angiopoietins and TIE2 in human and rat thyroids. In human goiters there was increased TIE2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of mRNAs for Tie2 and Ang1 in follicular cells. Since TIE2 expression is believed to be restricted to cells of endothelial lineage in adults, they examined its expression further in isolated follicular cells. TIE2 and ANG1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. In both human follicular cell cultures and rat thyroid cells, immunoblotting showed that TIE2 expression was increased by thyroid-stimulating hormone (TSH; 188540) and agents that increased intracellular cAMP. The authors concluded that TIE2 and ANG1 are expressed in thyroid epithelial and endothelial cells, and that TIE2 is regulated by TSH and cAMP in follicular cells. They also concluded that TIE2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis.
Interaction of hematopoietic stem cells (HSCs) with their particular microenvironments, known as stem cell niches, is critical for adult hematopoiesis in bone marrow. Arai et al. (2004) demonstrated that HSCs expressing the receptor tyrosine kinase TIE2 are quiescent and antiapoptotic and comprise a side population of HSCs that adhere to osteoblasts in the bone marrow niche. The interaction of TIE2 with its ligand, ANG1, induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, ANG1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggested that the TIE2/ANG1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the bone marrow niche.
Independently, Fukuhara et al. (2008) and Saharinen et al. (2008) showed that ANG1 bridged TIE2 molecules on the surface of adjacent endothelial cells at cell-cell contacts. In contrast, extracellular matrix-bound ANG1 located TIE2 at cell-substratum contacts in isolated cells. Fukuhara et al. (2008) reported that TIE2 preferentially activated AKT (see 164730) signaling at cell-cell contacts and ERK (see MAPK1; 176948) signaling at cell-substratum contacts. Saharinen et al. (2008) found that ANG1 induced phosphorylation of TIE2-associated eNOS (NOS3; 163729), a downstream substrate of AKT, in intercellular contacts of confluent cells. The authors concluded that the cellular microenvironment determines TIE2 signaling between activated angiogenic endothelial cells and quiescent endothelium.
Kim et al. (2011) found that the mouse cell surface serine protease epithin (ST14; 606797) cleaved Tie2. Immunoprecipitation analysis revealed that interaction of epithin and Tie2 required phorbol ester-mediated cell activation. Tie2 was predominantly expressed in endothelial cells, while epithin was often expressed on the surface of surrounding cells, including epithelial cells. Coculture experiments revealed that epithin expressed on mouse thymic epithelial cells could cleave Tie2 expressed on endothelial cells. Soluble epithin released to the culture medium did not cleave Tie2. Epithin-mediated Tie2 cleavage induced phosphorylation and activation of the truncated Tie2 protein independent of Ang1, resulting in downstream Tie2 signaling via the p85 subunit of PI3 kinase (PIK3R1; 171833). Knockdown of epithin reduced the ability of mouse epithelial cells to migrate through a confluent endothelial cell monolayer and reduced metastasis of mouse mammary tumor cells in vivo. Kim et al. (2011) concluded that epithin expressed on tumor cell surfaces can generate a pathway for metastasis directly by breaking down endothelial cell junctions via TIE2 cleavage and indirectly via activation of truncated TIE2, leading to downstream remodeling of the endothelial cell cytoskeleton and cell retraction.
Multiple Cutaneous and Mucosal Venous Malformations
Venous malformations, the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. In affected members of 2 unrelated families with multiple cutaneous and mucosal venous malformations (VMCM; 600195), Vikkula et al. (1996) identified a missense arg849-to-trp mutation (R849W; 600221.0001) in the kinase domain of TIE2. Using proteins expressed in insect cells, they demonstrated that the mutation resulted in increased activity of TIE2. They concluded that activating mutation in TIE2 caused inherited venous malformations in the 2 families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.
Calvert et al. (1999) studied 4 kindreds with inherited venous malformations and identified heterozygosity for the R849W mutation in 1 family. In another family the disease phenotype cosegregated with a different missense mutation (Y897S; 600221.0002), also located in the first kinase domain. Transfection experiments in COS-1 cells using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. Of the 2 remaining families, 1 excluded linkage to the TIE2 locus, providing evidence for the existence of at least 1 additional locus for dominantly inherited venous malformations.
Limaye et al. (2009) assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations (600195). Limaye et al. (2009) identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TEK hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TEK and the common, inherited R849W (600221.0001) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. Limaye et al. (2009) concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TEK pathways as potential therapeutic targets for venous malformations.
Wouters et al. (2010) analyzed the TEK gene in 26 affected individuals from 12 unrelated families with cutaneomucosal venous malformations and identified a heterozygous R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., 600221.0003 and 600221.0004). All mutations were located in the intracellular portion of TEK, 3 in the first tyrosine kinase domain, 3 in the kinase insert domain, and 1 in the C-terminal tail. Although the level of ligand-independent hyperphosphorylation of TEK demonstrated with these VMCM-associated substitutions was highly variable, Wouters et al. (2010) observed no genotype-phenotype correlation.
Using endothelial cell cultures, mouse models, and ultrastructural examination of patient tissue biopsies, Natynki et al. (2015) analyzed 22 TEK mutations previously identified in patients with venous malformations. The data suggested that the development of TEK-associated venous malformations results from several molecular mechanisms that occur in tandem: AKT activation, which reduces the major endothelial cell-secreted smooth muscle cell-attractant PDGFB (190040); loss of plasma membrane TEK, which results in lower responsiveness to angiopoietin (see 601667) ligand-mediated regulation; and ERK1 (601795)/ERK2 (176948) activation, which negatively impacts endothelial cell morphology and extracellular matrix fibronectin (135600) and dysregulates the plasminogen (173350)/plasmin coagulation cascade. The authors noted that the venous malformation phenotypes these pathways mediate in patients were recapitulated in a spheroid-transplantation mouse model.
Primary Congenital Glaucoma 3E
By exome sequencing in a multiethnic cohort of 189 unrelated families with primary congenital glaucoma (see GLC3E, 617272), Souma et al. (2016) identified 10 heterozygous loss-of-function mutations in the TEK gene (see, e.g., 600221.0005 and 600221.0006) in 10 of the families. Copy-number variant analysis revealed no evidence for additional exon-spanning duplications or deletions. Souma et al. (2016) concluded that gain-of-function mutations in TEK result in venous malformations in nonocular tissues, whereas loss-of-function mutations affect anterior chamber vascular development and result in primary congenital glaucoma.
Souma et al. (2016) generated Tek hemizygous and conditional knockout mice and analyzed their aqueous humor outflow pathways. Confocal microscopy revealed that Tek-haploinsufficient mice developed a severely hypomorphic canal with convolutions and focal narrowing, whereas the Schlemm canal was completely absent in Tek-knockout mice, consistent with a requirement for TEK as well as gene-dosage sensitivity during Schlemm canal development. Serial histologic sections of the iridocorneal region in Tek-haploinsufficient mice showed a hypoplastic Schlemm canal and trabecular meshwork, and analysis of intraocular pressures by rebound tonometry showed a 25% elevation compared to control mice. Souma et al. (2016) concluded that reduced TEK signaling causes developmental defects of aqueous humor outflow structures and correlates with elevated intraocular pressure.
In affected members of 2 unrelated families with multiple venous malformations of the skin and mucous membranes (VMCM; 600195), previously studied by Boon et al. (1994) and Gallione et al. (1995), respectively, Vikkula et al. (1996) identified heterozygosity for a 2545C-T transition in the TEK gene, resulting in an arg849-to-trp (R849W) substitution in the kinase domain of the receptor. The mutation was not found in 138 controls. Using proteins expressed in insect cells, they demonstrated that the mutation results in increased phosphorylation activity of TEK and therefore represents an activating mutation.
In affected members of a family with VMCM, Calvert et al. (1999) identified heterozygosity for the R849W mutation.
In 14 affected individuals from 6 unrelated families with VMCM, Wouters et al. (2010) identified heterozygosity for the R849W mutation in exon 15 of the TEK gene. In addition to mucocutaneous lesions, venous malformations were also present in the lung in 2 patients and in the brain in 1 patient. Haplotype analysis did not support the hypothesis that the R849W change is due to a single common ancestral allele, and Wouters et al. (2010) concluded that 2545C is probably a hotspot region for mutations.
In an analysis of 22 TEK mutations previously identified in patients with venous malformations, Natynki et al. (2015) stated that inherited R849W mutations clustered with Y897 (see 600221.0002) single mutations, supporting the status of R849W as a 'predisposing' mutation that requires an additional (somatic) change to cause disease. They noted that this was further strengthened by the venous-malformation (VM) mouse model, in which both the Y897F variant and R849W showed low VM-formation capacity.
In a 3-generation family with multiple venous malformations of the skin and mucous membranes (VMCM; 600195), Calvert et al. (1999) identified an A-to-C transversion at nucleotide 2690 of the TEK gene, resulting in a tyr897-to-ser (Y897S) missense mutation within the first kinase domain. The A2690C substitution created a novel NlaIV restriction site. The mutation fully cosegregated with disease status within the family.
In a father and 2 sons with 15 to 30 localized cutaneous and mucosal venous malformations (VMCM; 600195), Wouters et al. (2010) identified heterozygosity for a 2690A-G transition in exon 17 of the TEK gene, resulting in a tyr897-to-cys (Y897C) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the Y897C mutation induced an approximately 13-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to mucocutaneous lesions, the father and 2 sons had venous malformations of the internal organs, including the intestines, kidney, thorax, and brain. D-dimer levels were elevated in all 3 patients. The paternal grandmother was also affected.
In a mother and 2 daughters with 1 to 4 cutaneomucosal venous malformations (VMCM; 600195), Wouters et al. (2010) identified heterozygosity for a 2744G-A transition in exon 17 of the TEK gene, resulting in an arg915-to-his (R915H) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the R915H mutation induced a 29-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to VMCMs, all 3 patients had a restrictive perimembranous ventricular septal defect.
In a mother and son from a Latino family (family 1) with primary congenital glaucoma (GLC3E; 617272), Souma et al. (2016) identified heterozygosity for a c.921C-A transversion (c.921C-A, NM_000459.4) in exon 7 of the TEK gene, resulting in a tyr307-to-ter (Y307X) substitution within the third EGF domain that was predicted to generate a protein lacking the entire intracellular protein kinase domain. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Analysis in HEK293 cells confirmed that the Y307X mutation does not produce a full-length intact protein. Onset of disease occurred in infancy in the mother and at age 4 months in the son, and glaucoma was unilateral in both. The unaffected maternal grandmother did not carry the mutation, and DNA was unavailable from the unaffected maternal grandfather.
In a mother and son from a European American family (family 10) with primary congenital glaucoma (GLC3E; 617272), Souma et al. (2016) identified heterozygosity for a c.448G-T transversion (c.448G-T, NM_000459.4) in exon 3 of the TEK gene, resulting in a glu150-to-ter (E150X) substitution. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Onset of disease occurred at age 2 months in the mother and at birth in the son, and glaucoma was bilateral in both. Variable expressivity was demonstrated in this family, with late-onset disease occurring in the boy's maternal aunt, who carried the E150X mutation, and no apparent disease in his 25-year-old sister, who carried the mutation. In addition, the maternal grandmother, for whom DNA was unavailable, had late-onset disease.
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., Suda, T. Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118: 149-161, 2004. [PubMed: 15260986] [Full Text: https://doi.org/10.1016/j.cell.2004.07.004]
Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum. Molec. Genet. 3: 1583-1587, 1994. [PubMed: 7833915] [Full Text: https://doi.org/10.1093/hmg/3.9.1583]
Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. Allelic and locus heterogeneity in inherited venous malformations. Hum. Molec. Genet. 8: 1279-1289, 1999. [PubMed: 10369874] [Full Text: https://doi.org/10.1093/hmg/8.7.1279]
Dumont, D. J., Anderson, L., Breitman, M. L., Duncan, A. M. V. Assignment of the endothelial-specific protein receptor tyrosine kinase gene (TEK) to human chromosome 9p21. Genomics 23: 512-513, 1994. [PubMed: 7835909] [Full Text: https://doi.org/10.1006/geno.1994.1536]
Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J., Breitman, M. L. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7: 1471-1480, 1992. [PubMed: 1630810]
Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, H. Z., Kodama, T., Shibuya, M., Takakura, N., Koh, G. Y., Mochizuki, N. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nature Cell Biol. 10: 513-526, 2008. [PubMed: 18425120] [Full Text: https://doi.org/10.1038/ncb1714]
Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. A gene for familial venous malformations maps to chromosome 9p in a second large kindred. J. Med. Genet. 32: 197-199, 1995. [PubMed: 7783168] [Full Text: https://doi.org/10.1136/jmg.32.3.197]
Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G. Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration. Blood 117: 1415-1424, 2011. [PubMed: 21097670] [Full Text: https://doi.org/10.1182/blood-2010-03-275289]
Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nature Genet. 41: 118-124, 2009. [PubMed: 19079259] [Full Text: https://doi.org/10.1038/ng.272]
Natynki, M., Kangas, J., Miinalainen, I., Sormunen, R., Pietila, R., Soblet, J., Boon, L. M., Vikkula, M., Limaye, N., Eklund, L. Common and specific effects of TIE2 mutations causing venous malformations. Hum. Molec. Genet. 24: 6374-6389, 2015. [PubMed: 26319232] [Full Text: https://doi.org/10.1093/hmg/ddv349]
Partanen, J., Armstrong, E., Makela, T. P., Korhonen, J., Sandberg, M., Renkonen, R., Knuutila, S., Huebner, K., Alitalo, K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Molec. Cell. Biol. 12: 1698-1707, 1992. [PubMed: 1312667] [Full Text: https://doi.org/10.1128/mcb.12.4.1698-1707.1992]
Ramsden, J. D., Cocks, H. C., Shams, M., Nijjar, S., Watkinson, J. C., Sheppard, M. C., Ahmed, A., Eggo, M. C. Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3-prime,5-prime-monophosphate. J. Clin. Endocr. Metab. 86: 2709-2716, 2001. [PubMed: 11397875] [Full Text: https://doi.org/10.1210/jcem.86.6.7552]
Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., Olsen, B. R., Alitalo, K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nature Cell Biol. 10: 527-537, 2008. [PubMed: 18425119] [Full Text: https://doi.org/10.1038/ncb1715]
Sato, T. N., Qin, Y., Kozak, C. A., Audus, K. L. tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc. Nat. Acad. Sci. 90: 9355-9358, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 90: 12056 only, 1993. [PubMed: 8415706] [Full Text: https://doi.org/10.1073/pnas.90.20.9355]
Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J. Clin. Invest. 126: 2575-2587, 2016. [PubMed: 27270174] [Full Text: https://doi.org/10.1172/JCI85830]
Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87: 1181-1190, 1996. [PubMed: 8980225] [Full Text: https://doi.org/10.1016/s0092-8674(00)81814-0]
Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Europ. J. Hum. Genet. 18: 414-420, 2010. [PubMed: 19888299] [Full Text: https://doi.org/10.1038/ejhg.2009.193]