{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Connector enhancer of kinase suppressor of Ras‐2 ("}, {"type": "b", "children": [{"type": "t", "text": "CNKSR2"}]}, {"type": "t", "text": "), also known as CNK2 or MAGUIN, is a multidomain scaffold protein that integrates multiple signaling pathways. Studies have shown that CNKSR2 is an “escape‐from–X inactivation” gene, suggesting that its biallelic expression in females may protect against the deleterious effects of loss‐of‐function mutations observed predominantly in males, with implications in tumor suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " CNKSR2 participates in Ras signaling by binding to key effectors such as Raf and proteins of the RalGDS family; through these interactions it is able to coordinate MAP kinase and small GTPase cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Its scaffolding functions are critical for organizing the postsynaptic machinery, thereby regulating dendritic spine development and synaptic assembly, which are essential for proper neuronal connectivity and cognitive function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, regulation of CNKSR2 protein stability plays an important role in cell proliferation. For example, CNKSR2 has been shown to interact with the E3 ubiquitin ligase Smurf2, which, rather than targeting it for degradation, stabilizes CNKSR2 and thereby supports proliferative signaling in breast cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Loss‐of‐function variants or deletions of CNKSR2 have been implicated in X‐linked neurodevelopmental disorders characterized by intellectual disability, language impairment, and epilepsy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", further underscoring its essential role in neuronal development.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, CNKSR2 functions as an essential integrator of signaling networks by bridging the MAPK cascade with small GTPase activities and by orchestrating the assembly of synaptic components. Defects in CNKSR2 expression or function can contribute to both oncogenic processes and neurodevelopmental disorders, highlighting its importance in maintaining cellular homeostasis across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrew Dunford, David M Weinstock, Virginia Savova, et al. 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