{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CADM4—also known as Necl‐4—is a member of the immunoglobulin superfamily of cell adhesion molecules that plays multifaceted roles in both the nervous system and in tumor suppression. In the peripheral nervous system, CADM4 is expressed by myelinating Schwann cells where it partners in trans with axonal adhesion molecules (such as Cadm3) to ensure proper axon–glia recognition, organize internodal domains, and regulate the growth and architecture of the myelin unit. Disruption of CADM4 function (or expression of truncated forms) leads to abnormal myelin structures (for example, focal hypermyelination, tomacula, or mislocalized ion channels) and impaired nerve conduction, although in some in vivo models its absence appears to be partly compensated, suggesting a complex regulation of myelination dynamics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In several epithelial and exocrine tissues, including the kidney and lung, CADM4 is localized at sites of cell–cell contact where it interacts with cytoskeletal adaptor proteins (for example, 4.1B) to maintain normal cell adhesion. In these contexts its loss or marked reduction is associated with tumor progression. In renal clear cell carcinoma and non‐small cell lung cancer, decreased CADM4 expression correlates with invasive features and poorer clinical outcomes, whereas restoration of CADM4 expression suppresses tumorigenicity. Similar tumor‐suppressive functions have been attributed to CADM4 in breast cancer, where reduced expression is linked to higher grade tumors and shorter disease‐free survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in myelination and tumor suppression, CADM4 has been implicated in modulating signaling pathways that control cell behavior. For instance, in endothelial cells CADM4 (Necl‐4) has been shown to influence the strength and outcome of vascular endothelial growth factor (VEGF)–induced signaling—thereby regulating contact inhibition, cell migration, and proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In injured nerves, changes in the expression of CADM4 and other necl family members suggest a role in axon regeneration and re‐establishment of axon–glia contacts"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and, at the blood–brain barrier, its downregulation in disease states such as experimental autoimmune encephalomyelitis indicates that CADM4 may contribute to the integrity of intercellular junctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, reviews of nectin and nectin‐like molecules summarize that while some family members are overexpressed in cancers, CADM4—and related molecules such as Necl‐1 and Necl‐2—more often function as tumor suppressors by promoting proper cell adhesion and polarity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CADM4 functions as a critical adhesion molecule: in the peripheral nervous system it regulates Schwann cell–axon interactions and myelin organization, while in epithelial tissues it supports normal cell–cell adhesion and suppresses malignant transformation. Its modulation of intracellular signaling further underscores its role as an important regulator of both developmental and pathological processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Neev Golan, Elena Kartvelishvily, Ivo Spiegel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.0571-13.2013"}], "href": "https://doi.org/10.1523/JNEUROSCI.0571-13.2013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23825401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23825401"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nimrod Elazar, Anya Vainshtein, Neev Golan, et al. 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