{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSyndecan‐3 (SDC3) is a transmembrane heparan sulfate proteoglycan that plays critical roles in the nervous system. It mediates neuronal development by acting either as a direct receptor or as a coreceptor for neurotrophic factors – for example, immobilized glial cell line–derived neurotrophic factor family ligands signal through SDC3 to promote cell spreading, neurite outgrowth, and cortical neuronal migration, thereby influencing cortical development (1:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " SDC3 also partners with pleiotrophin and midkine during midbrain development to support dopaminergic neuron survival and neurite extension, suggesting an important role in the establishment and repair of the nigrostriatal system (2:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, binding of the immunomodulatory peptide Y-P30 to SDC3—together with syndecan-2—and pleiotrophin facilitates neuritogenesis in developing neurons (3:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, in the context of neurodegeneration, SDC3, which is highly expressed in neurons, mediates the internalization of misfolded protein fibrils such as α-synuclein and tau through a lipid-raft dependent, clathrin-independent endocytic pathway (4:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while also modulating amyloid β aggregation and uptake in an apolipoprotein E isoform–dependent manner (5:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSDC3 is additionally involved in immune responses and inflammatory processes. On dendritic cells, it functions as a major attachment receptor for HIV-1 by binding the viral envelope glycoprotein gp120, thereby stabilizing the virus and facilitating its transmission to T cells (6:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In rheumatoid arthritis, its soluble form—abundantly expressed on synovial endothelial cells—binds pro-inflammatory chemokines, which may influence leukocyte trafficking and promote joint inflammation (7:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, SDC3 expression is notably increased in uterine tissues during labor, suggesting a role in modulating intercellular communication within the myometrium during parturition (8:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer and metabolic regulation, SDC3 exhibits multifaceted functions. Its transmembrane domain, characterized by a conserved GxxxG motif, drives strong dimerization and heteromeric interactions that likely contribute to the specificity and diversity of its downstream signaling (9:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while its intrinsically disordered regions enable binding to a wide range of partners (10:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Upregulated SDC3 expression has been observed in several cancers—including pancreatic (11:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", cases where it also appears as N-syndecan in pancreatic lesions (12:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and prostate malignancies (13:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "; 14:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "—and is implicated in promoting tumor aggressiveness, stemness, and chemoresistance, as similarly observed in ovarian cancer via the TRPM2-AS/miR-138-5p/SDC3 axis (15:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "; 16:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Moreover, in hypoxic tumor microenvironments, SDC3 expression is induced by hypoxia-inducible factors and is associated with proinflammatory macrophage profiles (17:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Beyond oncogenesis, preclinical and genetic studies indicate that SDC3 modulates energy balance, with null mouse models demonstrating altered feeding behaviors (18:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "and specific SDC3 polymorphisms correlating with female obesity and altered endocrine profiles (19:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maxim M Bespalov, Yulia A Sidorova, Sarka Tumova, et al. 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