PPP2R1A Human
Description
Introduction to PPP2R1A
PPP2R1A (Protein Phosphatase 2 Scaffold Subunit Aalpha) encodes the scaffolding Aα subunit of Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase regulating cellular signaling, growth, and DNA repair . PP2A holoenzymes consist of a catalytic (C), scaffolding (A), and regulatory (B) subunit, with PPP2R1A serving as the structural core for assembly .
Clinical Associations
PPP2R1A variants are linked to two primary disease categories:
Neurodevelopmental Disorders (NDDs)
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Core Features:
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Genotype–Phenotype Correlations:
Cancer
Biochemical Dysfunction Mechanisms
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NDDs: Loss of B55α binding reduces PP2A activity, destabilizing neuronal development . Striatin-binding variants alter synaptic plasticity, worsening cognitive deficits .
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Cancer: Mutations (e.g., p.P179R, p.S256F) disrupt B56 subunit binding, promoting unchecked kinase signaling (e.g., AKT/mTOR) .
Research Advancements
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NDD Studies:
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Cancer Studies:
Diagnostic and Therapeutic Implications
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Genetic Testing: PPP2R1A is included in NDD panels (e.g., Simons Searchlight) .
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Therapeutic Strategies:
Unresolved Questions
Product Specs
Q&A
What is the structural and functional role of PPP2R1A in the PP2A complex, and how do mutations disrupt its activity?
PPP2R1A encodes the scaffolding Aα subunit of the heterotrimeric PP2A phosphatase, essential for coordinating the catalytic (C) and regulatory (B) subunits. Mutations in PPP2R1A, particularly in the HEAT repeats (e.g., R183), impair binding to PP2A subunits, reducing phosphatase activity and promoting oncogenesis or neurodevelopmental disorders .
Key Mutational Hotspots
How do PPP2R1A mutations contribute to ATR inhibitor (ATRi) sensitivity in ovarian clear cell carcinoma (OCCC)?
PPP2R1A mutations (e.g., p.R183W) exacerbate S-phase stress and genomic instability when combined with ARID1A loss. Preclinical models show enhanced ATRi efficacy due to:
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Premature mitotic entry from defective cell cycle checkpoints .
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Reduced PP2A-mediated dephosphorylation of DNA damage response (DDR) targets .
CRISPR-prime editing in isogenic OCCC models validated this mechanism, with ATRi sensitivity correlating with PPP2R1A mutation status .
What experimental approaches are used to validate PPP2R1A mutation effects in neurodevelopmental disorders (NDD)?
To assess PPP2R1A variants linked to NDD:
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Biochemical assays: Measure PP2A phosphatase activity and binding to regulatory subunits (e.g., B55α) .
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CRISPR models: Introduce variants into neural progenitor cells to study neuronal differentiation and synaptic function .
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Structural modeling: Predict variant-induced conformational changes (e.g., R183Q disrupting HEAT repeat stability) .
Variant-Specific Outcomes
How do oncogenic PPP2R1A mutations differ from those causing NDD, and what drives this dichotomy?
| Feature | Oncogenic PPP2R1A | NDD PPP2R1A |
|---|---|---|
| Variant Type | Missense (e.g., R183W) | Missense/truncating |
| PP2A Activity | ↓ (partial loss) | ↓ (severe loss) |
| Cellular Impact | Tumor progression via DDR defects | Neurodevelopmental arrest via signaling pathway dysregulation |
| Tissue Tropism | Ovarian/endometrial cancers | Brain, heart |
Mechanistic Insight
Oncogenic mutations preserve residual PP2A function, allowing tumor growth but sensitizing to ATRi . NDD mutations cause catastrophic PP2A loss, disrupting neural development and survival pathways .
What are the challenges in interpreting PPP2R1A mutation data across cancers and neurodevelopmental cohorts?
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Heterogeneity in mutation impact:
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Context-dependent effects:
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Data gaps:
How can researchers design CRISPR screens to identify synthetic lethal interactions in PPP2R1A-mutant cancers?
Workflow for ATRi Sensitivity Screens
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Model Generation:
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Screen Design:
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Data Analysis:
What are the clinical implications of PPP2R1A mutations as biomarkers for ATRi therapy?
Recommendations
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OCCC patients: Test PPP2R1A and ARID1A mutations upfront for ATRi eligibility .
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NDD patients: Prioritize cardiac and neurological monitoring for R183Q carriers .
How do PPP2R1A mutations influence PP2A-B55 and PP2A-B56 complex functions differently?
Subunit-Specific Effects
Experimental Validation
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Co-IP assays: Measure PPP2R1A interaction with B55α/B56α in mutant vs. WT cells .
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Phospho-protein profiling: Track PP2A-B55 substrates (e.g., p-Akt, p-ERK) and PP2A-B56 substrates (e.g., β-catenin) .
What unresolved questions remain in PPP2R1A research, and how can they be addressed?
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Mechanistic Paradox: Why do partial PP2A losses (oncogenic) and complete losses (NDD) yield opposite phenotypes?
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Approach: Compare phosphoproteomes of PPP2R1A-mutant cancer vs. NDD cells.
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Tissue-Specific Effects: Why are PPP2R1A mutations enriched in OCCC/endometrial cancers?
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Approach: Model PPP2R1A mutations in organoid systems (e.g., fallopian tube vs. endometrial).
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Therapeutic Resistance: Do PPP2R1A mutations confer ATRi resistance in non-OCCC contexts?
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Approach: Screen ATRi efficacy across PPP2R1A-mutant cancer cell lines.
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Product Science Overview
PP2A is a heterotrimeric enzyme composed of three subunits:
- Catalytic Subunit (C Subunit): This subunit is responsible for the enzyme’s phosphatase activity.
- Structural Subunit (A Subunit): Also known as the scaffolding subunit, it coordinates the assembly of the catalytic subunit and a variable regulatory subunit.
- Regulatory Subunit (B Subunit): This subunit is variable and determines the substrate specificity, localization, and activity of the PP2A holoenzyme .
The A subunit, specifically the alpha isoform (PPP2R1A), is a 65 kDa protein that serves as a scaffold for the assembly of the PP2A holoenzyme. It is composed of 15 tandemly repeated HEAT sequences, which are degenerate motifs of 39 amino acids present in various proteins .
PP2A has a broad substrate specificity and is involved in numerous cellular functions. It acts as a tumor suppressor by dephosphorylating key proteins in oncogenic signaling pathways, such as Raf, MEK, and AKT . The regulatory subunit A alpha isoform (PPP2R1A) plays a crucial role in the formation and function of the PP2A holoenzyme, influencing its enzymatic activity and substrate specificity .
The human recombinant form of the regulatory subunit A alpha (PPP2R1A) is produced using recombinant DNA technology. This involves cloning the gene encoding PPP2R1A into an expression vector, which is then introduced into a host cell (such as E. coli or yeast) for protein production. The recombinant protein is subsequently purified for use in research and therapeutic applications.
Mutations in the PPP2R1A gene have been implicated in various cancers, including ovarian clear cell carcinoma. Studies have shown that PPP2R1A functions as an oncogene in certain contexts, contributing to the pathogenesis of these cancers . Understanding the structure and function of PP2A and its regulatory subunits is crucial for developing targeted therapies for cancer and other diseases.
