PIK3CB

Detailed Information

The PIK3CB gene is located on human chromosome 3q22.3 and encodes the β catalytic subunit (p110β) of phosphoinositide 3-kinase (PI3K), a member of the class IA PI3K catalytic subunit family. The full-length transcript of PIK3CB spans 3,213 bp and encodes a protein of 1,070 amino acids with an approximate molecular weight of 124 kDa. Structurally, p110β contains multiple conserved functional domains: an adaptor-binding domain (ABD) at the N-terminus that interacts with the p85 regulatory subunit, a Ras-binding domain (RBD), a C2 domain that facilitates membrane localization, a canonical phosphoinositide kinase catalytic domain, and a C-terminal PIK domain that regulates phospholipid substrate specificity. Bioinformatic predictions indicate that p110β is a hydrophilic acidic protein lacking transmembrane domains and a signal peptide, with secondary structure comprising approximately 40.5% α-helices and 36.8% random coils, consistent with its role as a multifunctional signaling scaffold. Compared with other PI3K catalytic subunits (e.g., PIK3CA, PIK3CD), PIK3CB exhibits unique evolutionary conservation, showing over 99% nucleotide homology with yak and bovine orthologs, while its expression profile varies significantly across mammalian tissues, notably high in spleen, uterus, and ovary.

Activation Mechanisms

PIK3CB activation is dual-dependent: it responds to receptor tyrosine kinase (RTK) signaling through interaction with the p85 regulatory subunit, and it can also be directly activated by G protein-coupled receptors (GPCRs) independent of p85. This dual activation positions p110β as a critical node integrating diverse signals. Under basal physiological conditions, PIK3CB is widely expressed in tissues such as heart, kidney, and muscle, but its cellular functions are context-dependent. For instance, in platelets, p110β mediates αIIb/β3 integrin signaling, stabilizing adhesion and aggregation critical for hemostasis; in neurons, it regulates synaptic plasticity and cell survival signaling. Notably, p110β exhibits both lipid kinase activity—phosphorylating PIP2 to generate PIP3—and protein kinase activity, enabling autophosphorylation, a dual enzymatic feature that underpins its multifunctional signaling capacity.

Biological Functions and Regulatory Mechanisms

PIK3CB serves as a hub in cellular signaling networks, mediating the PI3K/AKT/mTOR pathway to regulate cell survival, proliferation, metabolism, and migration. Upon growth factor or cytokine receptor binding, p110β is recruited to the plasma membrane, catalyzing PIP3 production, which recruits PH-domain-containing effectors such as AKT and PDPK1 to form signaling complexes. In metabolism, p110β acts as a scaffold in insulin signaling, regulating GLUT4 translocation independently of lipid kinase activity, thereby modulating peripheral glucose uptake. A particularly notable function is its GPCR-mediated signaling: p110β directly responds to ligands such as CXCL12, sphingosine-1-phosphate (S1P), and lysophosphatidic acid (LPA), linking chemokine networks to cell growth signals.

Figure 1. Domain architecture of class I PI3K catalytic subunits (p110α, β, δ, γ) and their regulatory interactions with p85 or p101/p84 subunits, highlighting activation mechanisms and downstream PIP3 signaling. (Vanhaesebroeck B, et al., 2021)

In the tumor microenvironment, PIK3CB promotes malignant progression via dual mechanisms: lipid kinase activity enhances AKT/mTOR-dependent survival and proliferation, while protein kinase activity regulates downstream targets involved in migration and invasion. Emerging studies reveal additional epigenetic regulation; in ovarian cancer, the RNA-binding protein hnRNPL forms phase-separated transcriptional condensates, binding noncoding RNAs at the PIK3CB promoter (paPIK3CB), significantly enhancing transcription. This process depends on hnRNPL’s intrinsic disordered region 2 (IDR2); deletion of a proline residue (IDR2delP) abolishes phase separation and suppresses PIK3CB transcription. During autophagy, PIK3CB regulates PtdIns3P levels to initiate autophagosome formation, while its scaffold function positively modulates autophagic flux independently of kinase activity.

Role in Disease

Aberrant PIK3CB expression is linked to various human diseases, especially cancers. In solid tumors, PIK3CB hyperactivation often cooperates with PTEN loss to drive tumor progression. Gastric cancer tissue microarray analysis showed a PIK3CB positivity rate of 63.8%, significantly higher than 45.7% in adjacent non-cancerous tissue, with expression levels correlating with tumor size, invasion depth, and clinical stage. High PIK3CB expression predicts poor prognosis, with a 5-year postoperative survival rate of 15.9% versus 70.3% for low-expression patients. In ovarian cancer, hnRNPL-driven PIK3CB overexpression activates PI3K/AKT-mediated glycolytic reprogramming, increasing lactate production and extracellular acidification rate (ECAR).

Beyond oncology, PIK3CB plays a key role in reproductive system development; in yak follicles, PIK3CB mRNA expression in granulosa cells increases with follicular maturation, suggesting its critical role in regulating granulosa cell proliferation and differentiation. In the cardiovascular system, p110β mediates platelet activation via thrombin and thromboxane A2 signaling, offering a potential antithrombotic target. In the nervous system, activation of PI3K/AKT via p110β promotes neuronal survival and axonal regeneration, indicating therapeutic potential for neurodegenerative diseases.

Clinical Applications and Translational Research

Targeting PIK3CB is a focus of translational research. Strategies include:

1. Small-molecule inhibitors: TGX-221 selectively inhibits p110β, blocking GPCR-mediated platelet activation without increasing bleeding risk; in ovarian cancer organoids, TGX-221 combined with PI-103 reverses glycolysis enhancement due to hnRNPL overexpression.
2. Nanodelivery systems: Redox-responsive Meo-PEG-S-S-PLGA nanoparticles efficiently deliver circPDE5A/PDE5A-500aa plasmids, promoting USP14-mediated PIK3IP1 deubiquitination and indirectly inhibiting PIK3CB signaling, suppressing tumor growth and metastasis in vitro and in vivo.
3. Combination therapy: PI3K inhibitors (e.g., LY294002) combined with chemotherapy (doxorubicin) synergistically enhance cytotoxicity in murine DLBCL models.

Challenges include essential physiological roles of p110β in insulin signaling and platelet aggregation, raising toxicity concerns. Additionally, PIK3CB amplification occurs in ~15% of diffuse large B-cell lymphoma (DLBCL); not all tumors rely on p110β signaling. Future development should focus on allosteric inhibitors for precise pathway modulation, tissue-specific delivery systems, and biomarker-guided patient stratification.

Research Challenges and Future Directions

Key questions remain regarding p110β’s kinase-independent functions, its dynamic regulation in tumor metabolism, and compensatory mechanisms in tissue-specific knockouts. Translational challenges include optimizing inhibitor selectivity, targeting phase-separated transcriptional condensates, and developing dual-function degraders (PROTACs) or CRISPR/dCas9 epigenetic editing tools. With advancing understanding of PIK3CB transcriptional regulation, post-translational modifications, and subcellular localization, precise targeting of PIK3CB holds promise for therapeutic breakthroughs in cancer, metabolic disorders, and thromboembolic diseases. Multidisciplinary approaches combining molecular biology, structural pharmacology, nanotechnology, and clinical stratification will be critical for translating these strategies from bench to bedside.