{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CASK is a highly conserved, multidomain scaffolding protein belonging to the MAGUK family that plays diverse roles in the development and function of neurons as well as other cell types. Functionally, CASK orchestrates synapse formation and maintenance by acting as a molecular hub that links transmembrane cell adhesion molecules (such as neurexin and, via its binding partners Mint1 and Caskin1, liprin‐α) to the cytoskeleton and signaling cascades. Through these interactions, CASK modulates presynaptic active zone assembly and dendritic spine stability—processes critical for neurotransmission and plasticity (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its synaptic roles, CASK participates in the regulation of intracellular calcium homeostasis and nuclear signaling. By directly binding to the C terminus of plasma membrane Ca²⁺-ATPase 4b (PMCA4b), CASK forms a physical link between the plasma membrane and the nucleus, thereby influencing Ca²⁺-dependent gene expression (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, modulation of CaMKII autophosphorylation by CASK is crucial for activity-dependent neuronal signaling underlying learning and memory (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Notably, mutations in the CASK gene are associated with a spectrum of neurodevelopmental disorders. Disruption of CASK function has been implicated in X‐linked intellectual disability, microcephaly, cerebellar and pontine hypoplasia, and FG syndrome—illustrating its essential role in proper brain development and function (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond the central nervous system, CASK influences ion channel trafficking and cell–cell adhesion. For example, by directly interacting with the C terminus of the cardiac sodium channel NaV1.5, CASK governs its surface expression at lateral membranes—thereby regulating cardiac excitability (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In epithelial and other cellular contexts, CASK associates with connexin43 to help target gap junction proteins to the plasma membrane, affecting processes such as cell migration and wound healing (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent studies further suggest that CASK may play roles in metabolic regulation and Ca²⁺ homeostasis in non‐neuronal cells, such as in sperm where its interaction with PMCA4b and JAM‐A is critical for controlling Ca²⁺ efflux and ATP consumption (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Collectively, these findings underscore CASK’s function as a multifunctional scaffold that integrates cell adhesion, ion homeostasis, and signal transduction pathways essential not only for synaptogenesis and neuronal plasticity but also for broader aspects of cell physiology. \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Patrick S Tarpey, Raffaella Smith, Erin Pleasance, et al. 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