PPP4C Human
Description
Functional Roles and Mechanisms
PPP4C modulates multiple signaling pathways through dephosphorylation:
Cellular Processes
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DNA Repair: Dephosphorylates γ-H2AX at DNA damage sites, facilitating repair .
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Wnt Signaling: Reduces AXIN1 levels, enhancing canonical Wnt activation .
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Immune Regulation: Affects T-cell differentiation and macrophage polarization .
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Embryogenesis: Essential for dorsal-ventral patterning and neural development .
Key Pathways
Cancer Biomarker
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Diagnostic Utility: Overexpressed in 14 cancer types (e.g., lung adenocarcinoma [LUAD], breast cancer) with high diagnostic accuracy (AUC >0.85) .
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Prognostic Impact: High PPP4C expression correlates with poor survival in LUAD (HR = 1.8, p < 0.001) and metastasis .
Immune Microenvironment
In LUAD, elevated PPP4C levels associate with:
Genetic Disorders
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Linked to 16p11.2 microdeletion syndromes (autism, developmental delays) .
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Implicated in episodic kinesigenic dyskinesia and glycogen storage disease XII .
Experimental Models
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Xenopus laevis: Ppp4c knockdown causes embryonic axis defects and impaired Wnt responses .
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Single-Cell RNA-seq: Malignant epithelial cells in LUAD show upregulated PPP4C-linked pathways (cell cycle, glycolysis) .
Therapeutic Targeting
PPP4C’s role in immune evasion and Wnt activation positions it as a candidate for:
Product Specs
Q&A
What experimental approaches are recommended for detecting PPP4C expression in human tissues?
PPP4C detection requires tissue-specific RNA and protein quantification. For RNA analysis, bulk RNA-seq (The Cancer Genome Atlas [TCGA] and Genotype-Tissue Expression [GTEx] datasets) and single-cell RNA-seq (Human Protein Atlas) are optimal . Protein detection involves Western blotting using antibodies targeting the ~35 kDa band under reducing conditions (e.g., Mouse Anti-Human PP4 Catalytic Subunit Monoclonal Antibody, MAB5074) . Validated cell lines include HeLa (cervical carcinoma), C2C12 (mouse myoblasts), and Nb2-11 (rat lymphoma) . Researchers should confirm antibody specificity via knockout controls or ppp4c morpholino (MO)-mediated translational blockade in model systems .
How is PPP4C linked to embryonic development, and what models are used to study this?
PPP4C regulates dorsoventral (DV) and anterior-posterior (AP) patterning via Wnt signaling. The Xenopus laevis embryo model is widely used due to conserved PPP4C function (99% homology to humans) . Key methodologies:
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Whole-mount in situ hybridization (WMISH): Maps ppp4c spatial expression (e.g., enrichment in neural crest and head regions during neurula stages) .
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Morpholino knockdown (KD): Blocks PPP4C translation by targeting the 5’ untranslated region (UTR), validated via rescue experiments with MO-resistant constructs .
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β-catenin overexpression assays: Tests PPP4C’s role in Wnt signaling by measuring axis duplication or target gene activation (e.g., Xnr3, Siamois) .
How does PPP4C regulate canonical Wnt signaling across cancer types, and how can contradictory findings be resolved?
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Positive correlation: CHOL, LGG, and LIHC show PPP4C-Wnt activation via Gene Set Enrichment Analysis (GSEA) .
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Negative correlation: GBM exhibits PPP4C-Wnt suppression, likely due to alternative regulatory subunits (e.g., PPP4R3α/β) .
Methodological resolution:
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Context-specific validation: Use Xenopus animal cap assays to test PPP4C-Wnt interactions under controlled β-catenin levels .
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Multi-omics integration: Combine RNA-seq, proteomics (AXIN1 quantification), and chromatin accessibility data to identify co-regulatory networks.
What challenges arise when studying PPP4C’s dual roles in embryogenesis and oncogenesis?
Key contradictions:
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PPP4C promotes Wnt-driven axis formation in embryos but is oncogenic in cancers like PAAD and LUAD .
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Embryonic lethality in PPP4C-deficient mice contrasts with its upregulation in most tumors .
Experimental strategies:
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Conditional knockout models: Tissue-specific PPP4C deletion in adult vs. embryonic tissues.
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Time-resolved transcriptomics: Compare PPP4C-associated DEGs during early embryogenesis (e.g., gastrulation) vs. tumor initiation.
How can researchers address variability in PPP4C’s prognostic significance across cancers?
Case example: PPP4C is a risk factor in LAML (HR = 2.1) but protective in THYM (HR = 0.6) .
Analytical solutions:
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Cohort stratification: Subdivide TCGA data by molecular subtypes (e.g., EGFR mutation status in LUAD).
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Multivariate regression: Adjust for confounders like tumor stage, immune infiltration, and co-mutations.
Table 1: PPP4C Diagnostic Accuracy in Select Cancers (TCGA/GTEx Data)
| Cancer Type | AUC | Sensitivity | Specificity |
|---|---|---|---|
| Bladder (BLCA) | 0.92 | 0.88 | 0.85 |
| Glioblastoma (GBM) | 0.89 | 0.82 | 0.91 |
| Pancreatic (PAAD) | 0.94 | 0.90 | 0.89 |
Table 2: PPP4C-Associated Biological Processes in Pan-Cancer DEGs
| Process | Cancer Types Enriched | Functional Role |
|---|---|---|
| Pattern specification | ACC, CHOL, LGG, UVM | Embryonic axis formation |
| Epidermal development | BRCA, BLCA, CESC, UCES | Tumor microenvironment remodeling |
| Synapse organization | 26/33 cancers | Neural crest cell migration |
Product Science Overview
The catalytic subunit of Protein Phosphatase 4 (PP4) is a protein composed of 307 amino acids with a molecular mass of approximately 35 kDa . It shares significant sequence similarity with other protein phosphatases, such as PP2A, indicating a conserved mechanism of action among these enzymes . PP4 consists of a catalytic subunit (PPP4C) that interacts with various regulatory proteins, such as PPP4R1 and PPP4R2, which determine substrate specificity and intracellular localization .
PPP4C is involved in several key cellular processes:
- Microtubule Organization: PP4 plays a role in the growth and organization of microtubules at centrosomes, which are essential for cell division and intracellular transport .
- DNA Damage Repair: PP4 is crucial for the repair of DNA double-strand breaks through homologous recombination and single-strand annealing pathways . It specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX), a marker for DNA damage .
- Apoptosis: PP4 is involved in the regulation of apoptosis, the programmed cell death process, which is vital for maintaining cellular homeostasis and preventing cancer development .
- TNF-alpha Signaling: PP4 participates in the signaling pathway of tumor necrosis factor-alpha, a cytokine involved in inflammation and immune responses .
Recombinant human PPP4C is widely used in research to study its function and regulation. By expressing and purifying the catalytic subunit in a controlled environment, researchers can investigate its interactions with other proteins and its role in cellular processes. This knowledge can contribute to the development of new therapeutic strategies for diseases associated with PP4 dysregulation.
