PRKCB

Detailed Information

The PRKCB gene is located on human chromosome 16p12-p11.2 and spans approximately 10,000 bp, comprising 18 exons that encode protein kinase C beta (PKCβ). Alternative promoter usage and splicing generate two major isoforms: PRKCBⅠ, encoded by exons 1–18, and PRKCBⅡ, which contains a unique 5′ exon replacing PRKCBⅠ’s first exon. These isoforms differ in tissue distribution and function, with PRKCBⅠ mainly cytosolic and PRKCBⅡ targeted to the membrane system. Promoter analysis reveals multiple conserved transcription factor binding sites (e.g., SP1, AP-1, NF-κB), and expression is finely regulated by epigenetic mechanisms such as DNA methylation and histone modifications. As a member of the conventional, calcium-dependent PKC (cPKC) subfamily, PRKCB activity relies on synergistic activation by Ca²⁺ and diacylglycerol (DAG). Structurally, PRKCB contains an N-terminal regulatory domain with C1 (DAG-binding) and C2 (Ca²⁺/phospholipid-binding) domains and a C-terminal catalytic domain with conserved serine/threonine kinase activity, enabling it to act as a central node in complex signaling networks.

Biological Functions and Signal Transduction Mechanisms

PKCβ, a multifunctional serine/threonine kinase, regulates numerous cellular processes. In B-cell receptor (BCR) signaling, it phosphorylates CARD11/CARMA1 at Ser-559, Ser-644, and Ser-652, promoting CARD11 translocation to lipid rafts, recruitment of the BCL10-MALT1 complex and MAP3K7/TAK1, and subsequent activation of IKK and NF-κB pathways, essential for B-cell activation. PRKCB also mediates negative feedback by phosphorylating BTK at Ser-180, altering its membrane localization and inhibiting activity. Under oxidative stress, PRKCB specifically phosphorylates p66Shc (Ser-36), triggering mitochondrial translocation and reactive oxygen species (ROS) production, leading to apoptosis. Epigenetically, PRKCB acts as a coactivator of the androgen receptor (AR), recruited to target gene promoters and phosphorylating histone H3 at Thr-6 (H3T6ph), which prevents LSD1/KDM1A-mediated demethylation of H3K4 and maintains transcriptional activation.

In metabolic regulation, PRKCB functions downstream of insulin signaling: mediating insulin-dependent DNA synthesis via RAF1-MAPK/ERK in muscle cells, negatively regulating insulin-stimulated GLUT4 translocation in adipocytes, and directly phosphorylating GLUT1 (SLC2A1) to enhance glucose uptake. In endothelial function, PKCΒ activation promotes RB1 phosphorylation, enhances VEGF-induced proliferation, and inhibits PI3K/AKT-dependent NOS3/eNOS regulation, contributing to endothelial dysfunction. PKCΒ also maintains triglyceride homeostasis by phosphorylating ATF2 to facilitate JUN-mediated target gene transcription and by phosphorylating KLHL3 to modulate WNK4 interaction and ion transport.

Disease Associations and Clinical Significance

Metabolic Diseases

PKCΒ plays a critical role in diabetic microvascular complications. Chronic hyperglycemia activates PKCΒ, leading to endothelial dysfunction and basement membrane thickening. In the retinal vasculature, PKCΒ activation increases vascular permeability and neovascularization, driving diabetic retinopathy. In glomeruli, PKCΒ mediates basement membrane thickening and mesangial expansion, contributing to diabetic nephropathy progression. PKCΒ inhibitor Ruboxistaurin has demonstrated efficacy in multiple randomized multicenter trials, significantly reducing microvascular complication incidence and progression, and has completed Phase III clinical trials as a potential first-in-class therapeutic.

Infectious Diseases

A 2025 study in Cell Reports Medicine revealed a critical role of PKCΒ in nontuberculous mycobacterial pulmonary disease (NTM-PD), especially Mycobacterium avium complex (MAC). Genome-wide association studies identified rs194800 at 16p21 as significantly associated with NTM-PD risk, with PRKCB as the causal gene. Mechanistically, PRKCB inhibits phagosome-lysosome fusion and phagosome acidification, promoting mycobacterial survival in macrophages. PRKCB knockout mice (Prkcb⁻/⁻) exhibit reduced lung pathology and bacterial load. Ruboxistaurin treatment in wild-type mice alleviates infection, with no effect in knockout mice, confirming target specificity and offering a host-directed therapeutic strategy for MAC disease.

Tumorigenesis and Progression

Aberrant PRKCB expression in various cancers promotes proliferation, apoptosis resistance, and invasion. In glioblastoma (GBM), PRKCB and AKT1 form a key signaling node; asiatic acid (AA) suppresses tumor growth by modulating astrocytes and the AKT1-PRKCB pathway, showing high binding affinity (−7.53 kcal/mol) via molecular docking. In hematologic malignancies, PRKCB supports leukemia cell survival; in solid tumors, it facilitates angiogenesis and metastatic microenvironments, providing a rationale for PRKCB-targeted therapies.

Targeted Therapy Strategies and Drug Development

PRKCB-targeted approaches include small molecule inhibitors, gene silencing, and natural compound modulation. Ruboxistaurin (LY333531), a selective PRKCB inhibitor, has demonstrated safety and efficacy in diabetic microvascular trials and is being explored for MAC infection. It competitively binds PRKCB’s ATP pocket, blocking kinase activity without affecting protein expression. Ruboxistaurin reduces bacterial load and inflammation in infection models and acts synergistically with antibiotics. Asiatic acid (AA) also targets PRKCB in tumors, offering multitarget therapeutic potential. In nerve repair, PRKCB downregulation post-sciatic nerve injury impairs Schwann cell proliferation and migration, suggesting modulation of PRKCB may aid peripheral nerve regeneration.

Research Challenges and Future Directions

Despite progress, translational application faces challenges. PRKCB isoforms (βI, βII) and splice variants differ in localization, substrate specificity, and function, yet current drugs lack isoform selectivity, risking off-target effects. Its signaling networks are highly complex, with context-dependent or even opposing functions, requiring spatiotemporally precise interventions. Designing highly selective inhibitors is challenging due to conserved kinase domains. Future research focuses on allosteric inhibitors targeting non-kinase domains, tissue-specific delivery, and conditional gene regulation, alongside detailed mapping of PRKCB signaling in disease contexts. Advances in structural biology, chemical biology, and gene editing may enable precision PRKCB-targeted therapies for metabolic, infectious, and malignant diseases.

As a multifunctional signaling hub, PRKCB’s central role in physiology and pathology continues to be confirmed. Ongoing mechanistic and translational research will deepen understanding of complex disease networks, guide individualized therapies, and improve outcomes for patients with challenging diseases.

Reference

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2. Beyfuss K, Hood DA. A systematic review of p53 regulation of oxidative stress in skeletal muscle. Redox Rep. 2018 Dec;23(1):100-117.

3. Zaid Y, Senhaji N, Naya A, et al. PKCs in thrombus formation. Pathol Biol (Paris). 2015 Dec;63(6):268-71.