{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWTIP is a LIM‐domain protein originally identified as a WT1‐interacting partner in podocytes, and its domain architecture—with an N-terminal proline‐rich pre‐LIM region harboring a nuclear export signal and three C-terminal LIM domains—places it in the zyxin subfamily of cytoskeletal adaptors ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWTIP localizes at cell–cell contact sites such as adherens junctions and focal adhesions where it helps coordinate the assembly and stability of intercellular junctions. As a member of the broader Ajuba family of LIM proteins, which also includes AJUBA and LIMD1, it participates in tension‐dependent regulation of junctional complexes—a process that can influence epithelial–mesenchymal transitions and dynamic cell remodeling ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn response to environmental or injurious stress, such as lipopolysaccharide exposure in podocytes, WTIP undergoes regulated nucleocytoplasmic shuttling. It translocates from cell junctions into the nucleus in a process that depends on signaling cascades (for example, JNK activation) and intact microtubule-dependent transport. Once nuclear, WTIP interacts with transcription factors including WT1, FOXO1, and FOXO3a to modulate gene expression programs involved in cell cycle regulation, apoptosis, and cytoskeletal remodeling ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWTIP also engages in key signaling networks. It interacts intracellularly with receptor tyrosine kinase Ror2 to inhibit canonical Wnt signaling, thereby influencing developmental processes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. In podocytes, WTIP is functionally linked to the Hippo pathway; its association with phosphorylated nephrin recruits Hippo kinases such as Lats1 and modulates YAP1 activity—a mechanism that helps convert mechanical cues at the cell surface into transcriptional responses ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. Moreover, in developing cardiac tissues, WTIP interacts with chromatin factors such as ASXL2 to modulate retinoic acid signaling ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of WTIP is implicated in disease. In the kidney, aberrant expression or mislocalization of WTIP contributes to podocyte injury, foot process effacement, and compromised filtration barrier function ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]. In cancer contexts, reduced WTIP expression—as seen in non–small‐cell lung cancer—leads to increased AKT activity and reduced tumor suppressor FOXO1 signaling ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]. In acute myeloid leukemia, both loss of function and the formation of an oncogenic UBA2–WTIP fusion protein (which leads to enhanced STAT and ERK pathway activity) have been reported, while altered interactions with centrosomal components may also affect BRCA2‐linked pathways ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]. Finally, a novel variant in WTIP has been associated with hypertrophic cardiomyopathy, implicating its role in noncanonical Wnt signaling in the heart ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, WTIP emerges as a versatile scaffold molecule that integrates signals from cell adhesion sites, the actin cytoskeleton, and mechanotransduction pathways with nuclear transcriptional events. By orchestrating responses to biophysical and biochemical cues, WTIP regulates epithelial integrity, developmental processes, and cell proliferation, while its dysregulation contributes to kidney injury, tumorigenesis, and cardiac disease.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Manakan B Srichai, Martha Konieczkowski, Aparna Padiyar, et al. 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