{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAM15 is a membrane‐anchored metalloproteinase–disintegrin that exerts multifaceted roles in modulating cell adhesion, ectodomain shedding, extracellular matrix remodeling, and signal transduction across diverse physiological and pathological contexts. In several tumor models, ADAM15 mediates the proteolytic cleavage of key cell adhesion molecules—such as E‐cadherin and fibroblast growth factor receptors—thereby initiating downstream receptor activation (e.g., HER2/HER3) and MAPK/ERK signaling to promote cell migration, invasion, and metastasis ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "}. Differential expression and alternative splicing of ADAM15 have been linked to aggressive phenotypes in prostate, breast, and ovarian cancers; in these settings, down‐regulation of ADAM15 attenuates cell motility and reduces metastasis, whereas its exosomal release may paradoxically suppress tumor cell adhesion by interfering with integrin α_vβ₃ binding ^{"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "}."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In vascular and inflammatory processes, ADAM15 contributes to pathological neovascularization and increased vascular permeability. Its proteolytic activity in endothelial and mesangial cells facilitates extracellular matrix degradation and promotes cell migration—functions that are implicated in conditions such as atrial fibrillation and sepsis ^{"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "}."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n The disintegrin domain of ADAM15 mediates specific interactions with integrins—for example, binding to α_vβ₃ via an RGD motif and to α₉β₁ through flanking residues—thereby participating directly in cell–cell and cell–matrix adhesion. In agreement, ADAM15 is found localized in adherens junctions together with VE‐cadherin, further indicating a role in maintaining intercellular contacts ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "}."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its extracellular functions, the cytoplasmic domain of ADAM15 interacts with Src family kinases and adaptor proteins such as Grb2, thereby linking its proteolytic and adhesion‐related activities to intracellular signaling cascades. This crosstalk is exemplified in GPCR–EGFR transactivation pathways, where ADAM15 associates with and modulates signals that regulate cell motility and survival ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "}."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, context‐dependent roles for ADAM15 have been observed. In models of cartilage homeostasis, overexpression of ADAM15 enhances chondrocyte adhesion to collagens and increases cell viability under stress, suggesting a protective role in joint remodeling ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "}. Conversely, in ovarian cancer cells, ADAM15 expression can diminish integrin α_vβ₃–mediated adhesion and thereby modulate cell spreading and migration ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "}."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore ADAM15 as a critical mediator that integrates proteolytic shedding, integrin interactions, and intracellular signaling to influence cancer progression, vascular remodeling, and tissue homeostasis. Its multifunctional properties, including regulation by alternative splicing and differential localization at cell–cell contacts, make ADAM15 a promising target for therapeutic intervention in diverse pathological conditions ^{"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "}.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Abdo J Najy, Kathleen C Day, Mark L Day "}, {"type": "b", "children": [{"type": "t", "text": "The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M801329200"}], "href": "https://doi.org/10.1074/jbc.M801329200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18434311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18434311"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Thorsten Maretzky, Guangli Yang, Ouathek Ouerfelli, et al. 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