{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HepaCAM—also known as GlialCAM—is a multifunctional immunoglobulin‐like cell adhesion molecule whose roles extend from the regulation of ion channel activity in glial cells to the modulation of cellular adhesion, proliferation, and migration in various tissues. In the nervous system, hepaCAM serves as an essential chaperone and auxiliary subunit for both the MLC1 protein and the ClC‐2 chloride channel. Through direct binding interactions, it ensures proper trafficking and stable localization of these proteins at astrocyte–astrocyte and astrocyte–oligodendrocyte junctions, thereby regulating chloride currents, cell volume, and gap junction coupling. This function is critical for maintaining glial homeostasis, and its disruption underlies the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts (MLC) as mutations in either MLC1 or HEPACAM lead to mislocalization of the channel complex and abnormal ion–water balance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, by modulating the gating and plasma membrane stability of ClC‐2 channels, hepaCAM influences ion fluxes that are of potential relevance to conditions such as primary aldosteronism—where mutations that increase ClC‐2 currents contribute to severe hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Beyond its roles in ion homeostasis, hepaCAM also functions as a tumor suppressor. In several carcinomas, its re‐expression restores cell–cell and cell–matrix adhesion, hampers cell proliferation and migration, and can even induce senescence through the modulation of key signaling pathways, including those governed by AKT, c‐Myc, and MAPK."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, the integrity of the actin cytoskeleton and proper gap junction formation—partly mediated by associations with connexin 43—are also affected by hepaCAM, underscoring its broad role in orchestrating cell adhesion and intercellular communication."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Finally, studies in prostate and other cancers have implicated hepaCAM in the regulation of invasion and metastasis via modulation of MAPK signaling, highlighting the importance of both its extracellular and cytoplasmic domains in these processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings position hepaCAM as a critical regulator of both glial ion channel function—linking its role in diseases such as MLC and possibly primary aldosteronism—and of tumor cell behavior, where its loss or dysfunction contributes to abnormal adhesion, unchecked proliferation, and enhanced invasiveness.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tania López-Hernández, Margreet C Ridder, Marisol Montolio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2011.02.009"}], "href": "https://doi.org/10.1016/j.ajhg.2011.02.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21419380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21419380"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elena Jeworutzki, Tania López-Hernández, Xavier Capdevila-Nortes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2011.12.039"}], "href": "https://doi.org/10.1016/j.neuron.2011.12.039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22405205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22405205"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maja B Hoegg-Beiler, Sònia Sirisi, Ian J Orozco, et al. 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