{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The FERMT3 gene encodes Kindlin‑3, a hematopoietic‐restricted adaptor protein that is essential for integrin activation and downstream signaling. Kindlin‑3 directly binds to distinct regions of the integrin β cytoplasmic tails, cooperating with talin to induce the high‐affinity conformation required for efficient ligand binding. This mechanism is critical for platelet functions—specifically, for integrin activation that underlies platelet aggregation, hemostasis, and thrombosis prevention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In leukocytes, Kindlin‑3 is equally pivotal; its interaction with β integrins (such as LFA‑1) promotes the shift to a high‐affinity state necessary for firm adhesion under shear flow, and its deficiency disrupts immune cell arrest and migration, as observed in leukocyte adhesion deficiency type III (LAD‑III) that manifests clinically with recurrent infections and bleeding."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " Moreover, Kindlin‑3 is indispensable for osteoclast function; by regulating the activation of multiple integrin classes, it orchestrates podosome and sealing‐zone formation required for bone resorption—its absence leading to osteopetrosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Kindlin‑3 also plays a role during embryonic vascular development where platelet activation mediated via Kindlin‑3 is critical for the proper separation of lymphatic and blood vessels"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and emerging evidence indicates that Kindlin‑3 contributes to integrin clustering and outside‑in signaling through associations with scaffolding proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, although traditionally viewed as hematopoietic‐specific, Kindlin‑3 is also expressed in endothelial cells where it further supports integrin‑dependent adhesion and tubular network formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings underscore that FERMT3/Kindlin‑3 is a central mediator of integrin activation and clustering, and its functional integrity is indispensable for normal hemostasis, immune surveillance, bone turnover, and vascular morphogenesis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Markus Moser, Bernhard Nieswandt, Siegfried Ussar, et al. 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