{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCalpain‐6 (CAPN6) is a unique, non‐proteolytic member of the calpain family that plays diverse roles in cytoskeletal regulation. In embryonic tissues, CAPN6 interacts with microtubules, stabilizing them through the promotion of α‐tubulin acetylation. Its overexpression retards cytokinesis, leading to the formation of multinucleated cells and abnormal microtubule bundling, whereas its suppression destabilizes microtubules and causes actin reorganization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn osteoclasts, CAPN6 localizes specifically to the sealing zone where it orchestrates cytoskeletal organization. The protein promotes cell spreading and actin ring formation, thereby enhancing bone resorption activity. Notably, glucocorticoids such as dexamethasone downregulate CAPN6 expression, leading to reduced microtubule stability and decreased levels of key integrin regulators, which collectively impair the resorptive function of these cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCAPN6 also serves as an important modulator of cell motility by influencing small GTPase signaling. By interacting with the microtubule-associated exchange factor GEF-H1, CAPN6 helps to regulate Rac1 activity, thus controlling lamellipodial formation and cell migration. Disruption of CAPN6 leads to aberrant Rac1 activation and altered RhoA activity, underscoring its critical role in the crosstalk between microtubules and the actin cytoskeleton."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the regulation of skeletal muscle development, CAPN6 functions as a negative modulator. Studies in Capn6-deficient mice reveal that loss of CAPN6 promotes enhanced embryonic muscle differentiation and accelerates the regeneration of adult skeletal muscles following injury, suggesting that CAPN6 normally acts to suppress muscle differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, in the context of inflammatory atherosclerosis, CAPN6 is induced in macrophages where it interferes with mRNA splicing by sequestering the essential EJC-loading factor CWC22 in the cytoplasm. This disturbance in splicing, particularly affecting components of Rac1 signaling, enhances macrophage pinocytosis and lipid deposition, thereby contributing to lesion formation and promoting atherogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cytoskeletal dynamics and cellular signaling, CAPN6 is also a positive regulator of ciliogenesis. Its expression is crucial for the formation of primary cilia, and deficiency in CAPN6 reduces the percentage of ciliated cells and compromises sonic hedgehog signaling, likely through diminished acetylation of α-tubulin—a key post-translational modification required for ciliary stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kazuo Tonami, Yukiko Kurihara, Hiroyuki Aburatani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain 6 is involved in microtubule stabilization and cytoskeletal organization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00992-06"}], "href": "https://doi.org/10.1128/MCB.00992-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17210638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17210638"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jung Min Hong, Steven L Teitelbaum, Tae-Ho Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-6, a target molecule of glucocorticoids, regulates osteoclastic bone resorption via cytoskeletal organization and microtubule acetylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.241"}], "href": "https://doi.org/10.1002/jbmr.241"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20814968"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20814968"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kazuo Tonami, Yukiko Kurihara, Satoshi Arima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.072561"}], "href": "https://doi.org/10.1242/jcs.072561"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21406564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21406564"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kazuo Tonami, Shoji Hata, Koichi Ojima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-6 deficiency promotes skeletal muscle development and regeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003668"}], "href": "https://doi.org/10.1371/journal.pgen.1003668"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23935533"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23935533"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takuro Miyazaki, Kazuo Tonami, Shoji Hata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI85880"}], "href": "https://doi.org/10.1172/JCI85880"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27525442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27525442"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Bo Hye Kim, Do Yeon Kim, Sumin Oh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of calpain-6 inhibits primary ciliogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMB Rep (2019)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31619317"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31619317"}]}]}]}