{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCBL‐B is an E3 ubiquitin ligase that plays a central role in signal transduction across diverse cell types. At the molecular level, CBL‐B possesses specialized domains—including a ubiquitin associated (UBA) region—that confer selectivity for polyubiquitin chains, distinguishing its binding properties from those of its close homologue c‐CBL. In T cells, for example, CBL‐B interacts with partners such as Crk‐L to negatively regulate signaling pathways, while in mast cells it translocates into lipid rafts to suppress FcεRI‐mediated activation. These structural and binding characteristics set the stage for its broader regulatory functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the adaptive immune system, CBL‐B functions as a crucial negative regulator that sets the threshold for T cell activation and helps enforce peripheral tolerance. Alterations in its activity—whether through point mutations such as the F328L variant implicated in type 1 diabetes or through diminished expression levels observed in systemic lupus erythematosus—are associated with failure of proper T cell anergy and the development of autoimmune disorders. Moreover, CBL‐B modulates T cell receptor signaling dynamics, with phosphorylation-dependent changes in its conformation directly impacting its E3 ligase activity and, consequently, T cell responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer and growth factor receptor signaling, CBL‐B plays multifaceted roles that impact tumor biology. In some hematologic malignancies, mutations in CBL‐B have been identified, suggesting a tumor‐suppressive function via regulation of activated tyrosine kinases. In solid tumors, CBL‐B is implicated in modulating the abundance and activity of key receptors. For instance, in non‐small cell lung cancer (NSCLC) treatment with icotinib, upregulation of CBL‐B is linked to inhibition of downstream proliferative mediators, while its knockdown in gastric cancer cells alters EGFR, ERK, and Akt signaling to diminish drug‐induced apoptosis. In breast and pancreatic cancers, microRNAs (miR‐675 and miR‐891b, respectively) target CBL‐B to modulate receptor stability and cell migration, and genetic variants in CBLB further correlate with patient outcomes. Additionally, CBL‐B can influence multidrug resistance by regulating the subcellular localization of proteins such as P‐glycoprotein, and it promotes the ubiquitination and degradation of receptors like TrkA in neuroblastoma cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "21"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in adaptive immunity and tumor cell signaling, CBL‐B also exerts important functions in innate responses and other hematopoietic lineages. In platelets, CBL‐B positively modulates signaling downstream of the GPVI receptor—contributing to proper aggregation and secretion processes—while in antifungal host defense it directs the ubiquitination of key pattern‐recognition receptors such as dectin‐1 and dectin‐2, thereby controlling the magnitude of innate immune responses. Moreover, genetic deletion of CBLB in natural killer (NK) cells has been shown to enhance their cytotoxicity against tumor targets, underscoring its role as a negative regulator of lymphocyte activation in multiple immunologic contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenying Zhang, Yuan Shao, Deyu Fang, et al. 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