{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHARPIN is a multifunctional adaptor protein that plays central roles in cellular signaling by acting as an integral component of the linear ubiquitin chain assembly complex (LUBAC). In this capacity, SHARPIN associates with HOIP and HOIL‐1L to catalyze linear polyubiquitination of targets such as NEMO, thereby promoting NF‑κB activation in response to diverse stimuli. Structural studies have revealed that its N‑terminal region adopts a pleckstrin homology‐like fold that mediates dimerization and provides a scaffold for protein–protein interactions. Moreover, SHARPIN directly binds to the conserved cytoplasmic region of integrin α‑subunits, preventing the recruitment of activators like talin and kindlin and thus maintaining β1‑integrins in an inactive state that is critical for proper lymphocyte migration and platelet function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, SHARPIN has emerged as a tumor‑associated gene whose expression is frequently upregulated across a range of malignancies including breast, prostate, melanoma, esophageal, colorectal, and cholangiocarcinoma. Its oncogenic functions are multifaceted: SHARPIN promotes the polyubiquitination of PTEN and facilitates p53 degradation via MDM2 stabilization, thereby enhancing proliferative and survival signaling. In addition, by modulating Rap1 activity and stimulating downstream p38 and JNK/c‑Jun pathways, it contributes to tumor cell migration, invasion, and metastasis. Paradoxically, in certain settings such as cutaneous basal cell carcinoma, diminished SHARPIN expression has been linked to a loss of tumor‑suppressive function, while in clear cell renal cell carcinoma, SHARPIN‐mediated ubiquitination of pVHL supports oncogenic HIF‑2α signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "20"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in modulating oncogenic and adhesion‐related pathways, SHARPIN is crucial for immune homeostasis and inflammatory regulation. Experimental models of SHARPIN deficiency reveal a predisposition to chronic dermatitis and heightened sensitivity to TNF‑induced keratinocyte apoptosis, phenomena that underlie autoinflammatory syndromes in both mice and humans. Altered SHARPIN expression is also implicated in atopic dermatitis through deregulated IL‑33/ST2 signaling, and rare genetic variants of SHARPIN have been associated with structural limbic system alterations linked to Alzheimer’s disease. Furthermore, by engaging in cross‐regulatory interactions with caspases and developmental regulators such as Eya1, SHARPIN contributes to broader aspects of cell survival, migration, and transcriptional control that are essential for both immune cell function and neural integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "27"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fuminori Tokunaga, Tomoko Nakagawa, Masaki Nakahara, et al. 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