{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSkeletal muscle‑ and kidney‑enriched inositol polyphosphate phosphatase (SKIP, also known as Inpp5k/Pps) plays a central role in negatively regulating insulin signaling in skeletal muscle. By dephosphorylating phosphatidylinositol 3,4,5‑trisphosphate (PIP3) to PI(3,4)P2, SKIP attenuates downstream Akt/protein kinase B activity, thereby reducing insulin‐stimulated glucose uptake, glycogen synthesis, and GLUT4 vesicle translocation. Moreover, following insulin stimulation, SKIP is recruited to membrane ruffles where it complexes with activated p21‑activated kinase 1 (Pak1) and dissociates from GRP78—events that collectively contribute to the timely termination of insulin signaling. In addition, the binding between SKIP and Pak1 can be specifically modulated by a short Pak1‐derived peptide, which, when expressed exogenously, enhances insulin signaling. Notably, SKIP expression is upregulated during endoplasmic reticulum stress via ATF6 and XBP1 activation, linking elevated SKIP levels to the pathogenesis of insulin resistance in skeletal muscle."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in insulin signaling, SKIP exerts a negative influence on muscle differentiation. Acting downstream of the myogenic regulator MyoD, SKIP inhibits IGF‑II transcription and thereby dampens IGF‑II‑mediated activation of the Akt–mTOR signaling cascade. Consequently, silencing of SKIP results in enhanced myoblast differentiation, as evidenced by increased IGF‑II production and the formation of thicker, multinucleated myotubes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSKIP functions outside of skeletal muscle as well. In the kidney, overexpression of the inositol polyphosphate 5‑phosphatase (SKIP/Inpp5k) specifically in collecting duct cells disrupts water homeostasis by modulating the arginine vasopressin receptor type 2 signaling pathway. These alterations lead to abnormal aquaporin‑2 expression and plasma membrane localization, ultimately impairing water reabsorption and contributing to defects in water metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond metabolic regulation and myogenesis, SKIP also influences cytoskeletal dynamics and nerve regeneration. In non‑muscle cells, the co‑chaperone SODD binds SKIP and suppresses its 5‑phosphatase activity, an interaction that facilitates optimal PI3K/Akt signaling and actin cytoskeletal reorganization required for cell migration. In the central nervous system, overexpression of SKIP in corticospinal neurons enhances axon growth and compensatory sprouting following traumatic injury by increasing the density of active cofilin in growth cones, thereby promoting actin polymerization and enabling microtubule extension into distal filopodia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takeshi Ijuin, Y Eugene Yu, Kiyohito Mizutani, et al. 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