{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRKCB isoforms (notably PKCβI and PKCβII) are critical mediators of diverse signal‐transduction events that regulate cellular homeostasis. For example, in myotonic dystrophy type 1, toxic CUG‐repeat RNAs trigger inappropriate activation of PKC (including PKCβII) that in turn hyperphosphorylates RNA‐binding proteins such as CUGBP1, contributing to pathogenic RNA gain‐of‐function effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, in human neutrophils, PKCβII serves as one of several isoforms that directly phosphorylate p47(phox) to facilitate NADPH oxidase activation and superoxide anion production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In endothelial cells, abnormal activation of PKCβ contributes to disrupted insulin signaling and reduced nitric oxide bioavailability in diabetes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while phosphorylation of Orai1 by PKCβ suppresses store‐operated Ca²⁺ entry."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In B cells, direct association of PKCβ with TRPC3 channels helps maintain its plasma membrane localization to support sustained extracellular signal–regulated kinase activation after B‐cell receptor engagement."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in acute signaling, PRKCB regulates transcriptional and epigenetic events that influence cell fate and oncogenesis. Androgen‐stimulated gene expression is promoted by PKCβ(I)–mediated phosphorylation of histone H3 at threonine 6; this modification prevents LSD1‐mediated demethylation of H3K4, preserving an active chromatin state."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " PKCβII also acts as a sensor of lipid peroxidation—by phosphorylating and activating ACSL4, it drives polyunsaturated fatty acid synthesis and amplifies lipid peroxidation in ferroptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In intestinal epithelial contexts, PKCβII promotes colon carcinogenesis through a Ras–Rac1–MEK signaling cascade that induces an invasive phenotype"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while in the tumor microenvironment of chronic lymphocytic leukemia, stromal PKCβII activates NF-κB to support malignant B-cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " The stability of activated PKCβII itself is modulated by its interaction with Hsp70, which binds the unphosphorylated turn motif to prolong enzyme lifetime."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Notably, altered expression of PRKCB, including reduced PKCβII levels in brain tissue and linkage of risk haplotypes, has been associated with autism"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In intestinal epithelial cells, EGF-mediated protection of tight junction integrity requires, in part, activation of PKCβI"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", and further, RUNX1 directly targets the PRKCB promoter to regulate apoptosis in myeloid cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, modulation of TRPC3 channel activity by PKCβ"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "and ceramide-mediated regulation of PKCβII’s subcellular localization in breast cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "further underscore its multifaceted role in oncogenic processes, with additional evidence implicating its involvement in prostate cancer progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these functions, PRKCB integrates signaling events in various disease and metabolic contexts. In vascular smooth muscle cells, elevated PKCβII levels under hyperglycemic conditions potentiate PDGF receptor upregulation and promote chemotaxis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and in dopaminergic neurons, PKCβ is essential for D₂ autoreceptor-mediated control of dopamine transporter recycling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In hematologic malignancies such as diffuse large B-cell lymphoma, increased PKCβII expression in tumor cells correlates with aggressive phenotypes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and reduced PKCβ activity has also been noted in major depression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Moreover, experimental evidence implicates PKCβ in diabetic complications—not only through disturbance of endothelial function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "but also via activation of a PKCβII–p66Shc pathway that impairs the reparative properties of muscular pericytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Finally, in Ewing sarcoma, aberrant transcriptional activation of PRKCB by the fusion oncogene EWSR1–FLI1 renders PKCβ a promising therapeutic target"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", while genome-wide association and mechanistic studies further identify PRKCB as a susceptibility locus in primary biliary cholangitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " Additionally, B-cell receptor signaling is fine-tuned by a PKCβ-dependent mechanism that sustains extracellular Ca²⁺ responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", collectively underscoring the diverse roles of PRKCB in health and disease.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "N Muge Kuyumcu-Martinez, Guey-Shin Wang, Thomas A Cooper "}, {"type": "b", "children": [{"type": "t", "text": "Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2007.07.027"}], "href": "https://doi.org/10.1016/j.molcel.2007.07.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17936705"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17936705"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alexandre Fontayne, Pham My-Chan Dang, Marie-Anne Gougerot-Pocidalo, et al. 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