TEK - TEK receptor tyrosine kinase |Elisa - Clia - Antibody - Protein

Background

TEK, also known as TEK receptor tyrosine kinase (also termed Tie2 in some literature), is a receptor tyrosine kinase (RTK) with significant roles in vascular development, maintenance, and angiogenesis. Receptor tyrosine kinases are a class of cell surface receptors that, upon ligand binding, activate intracellular signaling cascades through phosphorylation. Specifically, the TEK/Tie2 receptor is primarily expressed in endothelial cells, which line blood vessels, as well as in certain subsets of hematopoietic cells. Its ligand, angiopoietin, specifically angiopoietins-1 and -2 (ANGPT1 and ANGPT2), modulates TEK signaling and plays essential roles in vessel stabilization, endothelial survival, and inflammatory responses.

TEK signaling plays an essential role in regulating vascular quiescence and homeostasis. In developing and mature vasculature, TEK helps balance angiogenesis, where new blood vessels form from existing ones, with vascular stability and permeability. This function makes TEK a crucial player in several physiological and pathological processes, from wound healing to cancer and other angiogenesis-dependent diseases. Dysfunctional TEK signaling has been implicated in a range of vascular and inflammatory diseases, including tumor angiogenesis, diabetic retinopathy, and sepsis.

Protein Structure

The TEK (TEK) receptor tyrosine kinase is a transmembrane protein encoded by the TEK gene in humans. It belongs to the endothelial-specific RTK family and shares similarities with the Tie1 receptor, though Tie1 does not directly bind angiopoietins. The TEK protein is approximately 1124 amino acids in length, with a molecular weight of around 140 kDa. Its structural domains are organized as follows:

1. Extracellular Domain: The extracellular portion of TEK consists of several subdomains:

• Immunoglobulin-like (Ig-like) Domains: These domains play a role in ligand binding and have structural stability, which supports interaction with angiopoietins. The extracellular region of TEK includes two Ig-like domains that provide binding specificity for angiopoietins.
• Epidermal Growth Factor (EGF)-like Repeats: Located adjacent to the Ig-like domains, these EGF-like repeats contribute to the structural framework required for receptor dimerization and functional ligand binding.
• Fibronectin Type III Domains: These domains support the overall architecture of the extracellular region and contribute to ligand specificity and receptor clustering.

1. Transmembrane Domain: The transmembrane domain anchors TEK within the cell membrane. This domain is essential for maintaining the receptor's structural integrity and positioning, allowing the extracellular and intracellular domains to interact efficiently with ligands and downstream signaling partners.
2. Intracellular (Cytoplasmic) Domain: The intracellular region of TEK contains the tyrosine kinase domain, which is essential for catalytic activity. Upon ligand binding, this domain undergoes autophosphorylation on specific tyrosine residues, which triggers a cascade of downstream signaling events. These phosphorylated tyrosine residues then serve as docking sites for various signaling proteins, leading to activation of pathways such as PI3K/AKT and MAPK, which regulate cell survival, migration, and vascular permeability.

The highly conserved nature of these structural domains reflects the functional importance of TEK in maintaining endothelial cell stability and vascular integrity. The receptor undergoes conformational changes upon ligand binding, which activates the tyrosine kinase domain and initiates autophosphorylation, subsequently leading to downstream signaling cascades.

Classification and Subtypes

TEK belongs to the RTK family, specifically within the Tie receptor family, which includes two primary members: Tie1 and Tie2. TEK is primarily distinguished by its unique ligand-binding capabilities, where it interacts with angiopoietins (ANGPT1 and ANGPT2), in contrast to Tie1, which does not directly bind these ligands and has an unclear role in angiopoietin signaling. These receptors work in tandem to regulate angiogenesis, with TEK serving as the primary mediator of angiopoietin-dependent signaling.

Function and Biological Significance

TEK’s signaling is crucial for vascular homeostasis and remodeling. Its activation promotes vascular quiescence, a state where blood vessels are stable and non-permeable, which is essential for maintaining normal blood flow and preventing vascular leakage. ANGPT1, the primary agonist of TEK, promotes endothelial survival and strengthens cell-cell junctions, stabilizing blood vessels. Conversely, ANGPT2, a context-dependent agonist/antagonist, can either promote angiogenesis or destabilize vessels depending on the presence of VEGF (vascular endothelial growth factor) and other signaling molecules.

Some specific roles of TEK include:

• Endothelial Cell Survival and Anti-Apoptosis: TEK signaling via the PI3K/AKT pathway enhances cell survival, preventing apoptosis, particularly under stress conditions such as hypoxia or inflammation.
• Vascular Permeability and Barrier Function: TEK activation by ANGPT1 tightens endothelial cell junctions, reducing permeability and maintaining vascular integrity. This function is vital in preventing leakage in various tissues, including the brain and lungs.
• Angiogenesis and Vascular Remodeling: During development or in response to tissue damage, TEK activation promotes controlled angiogenesis. The receptor regulates the migration and proliferation of endothelial cells, facilitating the formation of new blood vessels while maintaining mature vessels' stability.
• Inflammatory Modulation: TEK modulates inflammation by influencing leukocyte adhesion and migration. In particular, ANGPT2-mediated STEK inhibition is associated with increased inflammatory responses, which are relevant in disease states like sepsis.

Clinical Issues

TEK dysregulation is associated with various vascular and inflammatory disorders, often leading to pathological angiogenesis or vascular destabilization. Some clinical issues related to TEK dysfunction include:

• Cancer: Abnormal TEK signaling contributes to tumor angiogenesis. Many tumors overexpress angiopoietins or aberrantly activate the TEK pathway, allowing tumors to recruit blood vessels, which supply nutrients and facilitate metastasis.
• Diabetic Retinopathy and Macular Edema: Excessive angiogenesis and increased vascular permeability mediated by dysregulated TEK signaling contribute to abnormal blood vessel growth and leakage in the retina, which can lead to vision loss.
• Sepsis and Inflammatory Disorders: In sepsis, ANGPT2 levels often rise, acting as a competitive inhibitor of ANGPT1 and TEK. This inhibition leads to vascular leakage, tissue edema, and heightened inflammatory responses, worsening the septic condition.
• Cardiovascular Diseases: Mutations or alterations in TEK signaling have been linked to various cardiovascular diseases, including atherosclerosis and heart failure. Vascular stability and endothelial function are compromised in these conditions, making the TEK pathway a therapeutic target for improving vascular health.

Summary

TEK receptor tyrosine kinase, is a critical endothelial receptor involved in maintaining vascular homeostasis, angiogenesis, and inflammatory modulation. With a complex protein structure encompassing extracellular ligand-binding domains and an intracellular tyrosine kinase domain, TEK efficiently transduces signals upon binding to its primary ligands, ANGPT1 and ANGPT2. Through downstream pathways like PI3K/AKT and MAPK, TEK regulates endothelial survival, vascular permeability, and response to inflammation. Aberrant STEK signaling is implicated in numerous pathologies, notably cancer, diabetic retinopathy, and sepsis, where vascular stability is compromised. Given its pivotal role in vascular biology, TEK represents a valuable target in therapies for conditions driven by vascular dysfunction, offering insights into angiogenesis, vessel maintenance, and endothelial cell regulation.