TIE2

Official Full Name

TEK receptor tyrosine kinase

Organism

Homo sapiens

GeneID

7010

Background

This gene encodes a receptor that belongs to the protein tyrosine kinase Tie2 family. The encoded protein possesses a unique extracellular region that contains two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin type III repeats. The ligand angiopoietin-1 binds to this receptor and mediates a signaling pathway that functions in embryonic vascular development. Mutations in this gene are associated with inherited venous malformations of the skin and mucous membranes. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

Synonyms

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

Bio Chemical Class

Kinase

Protein Sequence

MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRDFEALMNQHQDPLEVTQDVTREWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQQASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGSFIHSVPRHEVPDILEVHLPHAQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGECICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNEACHPGFYGPDCKLRCSCNNGEMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIEVNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNHTDHFSVAIFTIHRILPPDSGVWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKKLLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTASIGLPPPRGLNLLPKSQTTLNLTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSVLLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPPQPENIKISNITHSSAVISWTILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGSSNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSAEEAA

Open

Disease

Breast cancer, Chronic arterial occlusive disease, Ischemia, Mature B-cell lymphoma, Myelodysplastic syndrome, Myeloproliferative neoplasm, Retinopathy, Rheumatoid arthritis, Sepsis, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

1 +

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Detailed Information

The TIE2 gene, also known as TEK, is located on human chromosome 9p21.2 and encodes a transmembrane protein belonging to the receptor tyrosine kinase family. The protein structure of TIE2 includes a unique extracellular domain consisting of two immunoglobulin-like structures, three epidermal growth factor (EGF)-like repeat sequences, and three fibronectin type III repeats. The intracellular region contains a highly conserved tyrosine kinase domain responsible for activating downstream signaling through autophosphorylation. The ligands for TIE2 are members of the angiopoietin family, including ANGPT1, ANGPT2, and ANGPT4, with ANGPT1 serving as the primary agonist, mediating receptor dimerization and phosphorylation. ANGPT2, however, can act as either an agonist or antagonist depending on the specific microenvironment. Splice isoforms of TIE2 produce a soluble extracellular domain, which functions as an endogenous decoy receptor to modulate the signal intensity.

Physiological Functions and Regulatory Mechanisms

TIE2 plays a central role in both embryonic vascular development and postnatal vascular homeostasis. In terms of vascular maturation and stability, TIE2 activation in resting blood vessels involves tight junctions between endothelial cells, promoting ANGPT1-mediated cross-cell activation, which preferentially activates the PI3K/AKT signaling pathway. This enhances endothelial cell survival and maintains vascular integrity. Pericytes, which also express functional TIE2, activate the Akt/FOXO3A signaling axis to inhibit pericyte migration, promoting endothelial-pericyte adhesion, thereby stabilizing blood vessel structure. Regarding angiogenesis regulation, under hypoxic or inflammatory conditions, ANGPT2 competes with ANGPT1 for binding to TIE2, reducing vascular stability and promoting sprouting angiogenesis. During this process, TIE2 signaling switches to activate FAK and ERK pathways, promoting endothelial cell migration. Notably, pericyte-specific TIE2 deficiency enhances cell mobility and accelerates pathological angiogenesis in tumor models via the calpain1/FOXO3A pathway.

Figure 1. Illustration of Ang-Tie2 signaling. (Duran CL, et al., 2021)

TIE2 is also involved in immune-vascular interactions. Monocytes expressing TIE2 (TEMs) have been shown to play a critical role in tumor angiogenesis. Under hypoxic conditions, ANGPT2 recruits TEMs to the tumor microenvironment, where they secrete matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), and other factors that directly promote new blood vessel formation.

Pathological Mechanisms and Disease Associations

TIE2 dysfunction is closely linked to various diseases. In hereditary vascular malformations, approximately 50% of patients with cutaneous-mucosal venous malformations carry somatic mutations in the TIE2 gene, leading to constitutive kinase activation, which causes vasodilation and thrombosis. In tumors, TIE2 expression is significantly upregulated in highly vascularized cancers such as gastric cancer and glioblastoma, where it correlates positively with microvascular density (MVD). Clinical studies have shown that TIE2 protein levels increase with the degree of tumor differentiation and lymph node metastasis, suggesting its potential as a prognostic biomarker. In retinal diseases, pericyte-specific TIE2 knockout mouse models demonstrate delayed retinal angiogenesis and abnormal vessel branching post-birth, further confirming the essential role of pericyte TIE2 in vascular normalization.

Clinical Translation and Targeted Therapy

Therapeutic strategies targeting TIE2 are primarily focused on inhibiting pathological angiogenesis, especially in cancer treatment. Angiopoietin 2-neutralizing monoclonal antibodies (such as CovX-Bodies) have shown significant reduction in TEM recruitment and tumor growth in breast cancer and pancreatic cancer models. When combined with anti-VEGF drugs (like Sorafenib), these therapies synergistically enhance anti-angiogenic effects and are currently undergoing phase II clinical trials. Moreover, gene delivery systems utilizing TIE2 promoters to drive interferon-alpha (IFN-α) expression specifically in TEMs have demonstrated localized drug delivery in glioma and breast cancer models, thereby reducing systemic toxicity. Considering the dual role of TIE2 in vascular homeostasis, new therapeutic agents, such as angiopoietin-mimicking peptides, are being developed to treat diabetic retinopathy, aiming to restore vascular stability without completely inhibiting the signal.

Challenges and Future Perspectives

Despite the promising therapeutic potential of targeting TIE2, several challenges remain. The function of ANGPT2 is highly dependent on local factors such as VEGF levels, and its pro-angiogenic or anti-angiogenic effects must be precisely regulated in various tissues and pathological conditions. Furthermore, the complexity of targeting pericyte TIE2 must be considered; while its deficiency may inhibit physiological vascular maturation, it unexpectedly promotes tumor angiogenesis, underscoring the need for detailed tissue-specific signaling network analysis. Additionally, resistance to anti-ANGPT2 monotherapy is a concern, as compensatory ANGPT1 upregulation may occur. Future studies need to explore "angiogenesis cocktail therapies" that combine VEGF, Notch, and other pathways to overcome resistance and improve therapeutic outcomes.

In summary, TIE2's critical role in vascular development and homeostasis makes it an important target for the treatment of numerous diseases, particularly cancer and vascular-related disorders. By precisely modulating TIE2 signaling pathways, more effective therapies may be developed in the future. However, overcoming the challenges of microenvironment-dependent effects, tissue-specific targeting, and resistance mechanisms will require further research and clinical validation.

Reference

Joussen AM, Ricci F, Paris LP, et al. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021 May;35(5):1305-1316.
Duran CL, Borriello L, Karagiannis GS, et al. Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination. Cancers (Basel). 2021 Nov 16;13(22):5730.

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