{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTIE1 is an endothelial‐restricted receptor tyrosine kinase that plays a pivotal modulatory role in vascular development and angiogenesis. It functions mainly by interacting with its close homolog TIE2 to promote angiopoietin‐(Ang)1–mediated vascular stabilization under quiescent, non‐inflammatory conditions, while its regulated ectodomain cleavage and subsequent processing in response to inflammatory and growth factor stimuli (such as VEGF) shift the balance of Tie2 activation and contribute to vessel remodeling and leakage. This dynamic regulation is central to both normal vessel maturation and pathologic vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTIE1 also exerts intracellular control over endothelial cell behavior by modulating gene expression and cell–cell junction integrity. Beyond its extracellular regulatory functions, TIE1 is subject to additional layers of control including regulation by a natural antisense long noncoding RNA that binds its mRNA to influence transcript levels and endothelial junction formation, as well as through post‐translational modifications. Notably, phosphorylation of TIE1 at a threonine residue (T794) via a Rac1/PAK1 signaling cascade emerges as a novel mechanism required for proper capillary morphogenesis and for regulating the endothelial–mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant TIE1 function is increasingly recognized as a contributing factor in multiple pathological contexts. In various cancers—including metastatic breast, colorectal, cervical, ovarian, and even certain gastrointestinal stromal tumors—aberrant TIE1 expression, either as full‐length or truncated constitutively active forms, influences tumor angiogenesis, vascular normalization, and metastasis. In some settings, TIE1 serves as an inhibitor of Tie2 signaling by forming heterocomplexes; however, its proteolytic shedding can relieve this inhibition and thereby enhance pro‐angiogenic signaling. These mechanisms underscore how TIE1 not only modulates vascular stability but also directly contributes to tumor progression and chemoresistance, as demonstrated in studies of experimental metastasis, GIST, and nasopharyngeal as well as cervical cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and expression studies further implicate TIE1 in a range of vascular and lymphatic disorders. Altered TIE1 localization and expression have been observed in placental development and venous structures, where they are thought to influence proper vascular patterning. In addition, loss‐of‐function variants and abnormal TIE1 expression have been linked to lymphatic malformations, lymphedema, and varicose veins. Moreover, modulation of endothelial inflammatory responses via TIE1, as evidenced by its impact on proinflammatory gene expression and monocyte chemoattractant protein production, highlights its role as a mediator of vascular inflammation that may underlie the progression of various vascular diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Emilia A Korhonen, Anita Lampinen, Hemant Giri, et al. 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