{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTEK (also known as Tie2) is an endothelial‐specific receptor tyrosine kinase essential for vascular development and homeostasis. It transduces signals from its ligands—primarily angiopoietin‑1 and angiopoietin‑2—to regulate endothelial cell survival, migration, and differentiation. In the presence of supportive extracellular matrix and cell–cell contacts, TEK activation initiates downstream cascades (including PI3K/Akt and Erk pathways) that promote cell–matrix adhesion, strengthen intercellular junctions, and enforce vascular quiescence. Such exquisitely balanced signaling is critical for the formation of a mature, stable vasculature and for maintaining barrier integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n\nTEK signaling also exerts pivotal functions in pathological settings—most notably in cancer—where it contributes to tumor angiogenesis, vascular remodeling, and metastasis. Its expression on a specialized subpopulation of monocytes (TIE2‑expressing monocytes, TEMs) and its participation in tumor microenvironments (such as at TMEM sites where tumor cells intravasate) underscore its role in driving aberrant neovascularization and in modulating vascular permeability. Moreover, the context‐dependent actions of angiopoietin‑2—acting as either a weak agonist or an antagonist of TEK—illustrate the complexity of its regulation in inflammatory and tumor settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "23"}]}, {"type": "t", "text": "\n\nMutations and dysregulation of TEK signaling have been implicated in a range of vascular anomalies and ocular disorders. Altered TEK function—whether manifest as ligand‐independent hyperactivation or as loss of proper subcellular trafficking and integrin cross‐talk—leads to malformations such as venous malformations and primary congenital glaucoma. In these contexts, improper mural cell recruitment, defective extracellular matrix interactions, and imbalance within downstream pathways (including MAPK and AKT) culminate in structurally compromised and leaky vessels. Notably, therapeutic strategies aimed at modulating TEK activity (for example, by employing Tie2 agonists or inhibitors of negative regulators such as VE‑PTP) have shown promise in normalizing vascular integrity in both tumor and ocular settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "36"}]}, {"type": "t", "text": "\n\nBeyond vascular development and cancer, aberrant TEK signaling contributes to systemic vascular dysfunction in conditions such as sepsis and inflammatory disorders—and even influences non‐endothelial processes such as satellite cell quiescence in tissue repair. In sepsis, for example, disruption of the TEK axis is associated with microvascular thrombus formation, vascular leakage, and coagulopathy, while pharmacologic restoration of TEK activity can normalize these responses without inducing bleeding. Collectively, these findings extend the impact of TEK beyond developmental angiogenesis to include roles in maintaining vascular integrity during systemic inflammation and in facilitating regenerative processes, thereby highlighting it as a promising therapeutic target in diverse clinical scenarios."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "41"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Yu, J Varughese, L F Brown, et al. 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