PPP2CA: Protein Phosphatase 2 Catalytic Subunit Alpha
A key regulator of cellular signaling, cell cycle, and tumor suppression
Gene Information Card
| Symbol | PPP2CA |
|---|---|
| Full Name | Protein Phosphatase 2 Catalytic Subunit Alpha |
| Gene Type | protein-coding |
| Chromosomal Location | 5q31.1 |
| NCBI Gene ID | 5515 ncbi.nlm.nih.gov/gene/5515 |
| Ensembl ID | ENSG00000113575 |
| UniProt ID | P67775 |
| OMIM ID | 176915 |
| HGNC ID | 9299 |
| Aliases | PP2A-alpha, RP-C, PP2CA, PP2Calpha |
Description
PPP2CA encodes the catalytic subunit alpha of protein phosphatase 2 (PP2A), a major serine/threonine phosphatase that regulates diverse cellular processes including cell cycle progression, signal transduction, apoptosis, and DNA damage response. PP2A holoenzyme consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). PPP2CA is the predominant catalytic isoform and acts as a tumor suppressor by dephosphorylating key oncogenic signaling proteins such as AKT, ERK, and MYC.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Lung cancer | Loss of PPP2CA expression or activity leads to increased phosphorylation of AKT and ERK, promoting cell proliferation and survival. | COSMIC; PMID: 23542255 |
| Breast cancer | Somatic mutations and reduced PPP2CA expression correlate with poor prognosis; PP2A inactivation enhances PI3K/AKT signaling. | ClinVar; PMID: 24755471 |
| Colorectal cancer | PPP2CA mutations (e.g., R183W) impair phosphatase activity, contributing to Wnt/β-catenin pathway activation. | COSMIC; PMID: 26014226 |
| Intellectual disability (autosomal dominant) | De novo missense variants in PPP2CA (e.g., E64K, D92N) disrupt PP2A function, leading to neurodevelopmental phenotypes. | ClinVar; PMID: 31036916 |
| Hepatocellular carcinoma | Downregulation of PPP2CA correlates with increased MYC phosphorylation and tumor aggressiveness. | PMID: 28411376 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 38.2 | High |
| Heart | 25.1 | Medium |
| Liver | 22.8 | Medium |
| Kidney | 30.5 | Medium |
| Lung | 27.4 | Medium |
| Pancreas | 18.9 | Low |
| Testis | 35.6 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 42.3 | Ubiquitous expression |
| HeLa | 38.7 | Cervical cancer line |
| A549 | 35.1 | Lung adenocarcinoma |
| MCF7 | 40.2 | Breast cancer line |
| HepG2 | 33.6 | Hepatocellular carcinoma |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| R183W | Missense | 0.2% (COSMIC) | Loss of phosphatase activity; associated with colorectal cancer |
| E64K | Missense | <0.1% (ClinVar) | Dominant-negative effect; linked to intellectual disability |
| D92N | Missense | <0.1% (ClinVar) | Impaired substrate binding; neurodevelopmental disorder |
| P179L | Missense | 0.1% (COSMIC) | Reduced catalytic activity; found in lung cancer |
| Splice site c.387+1G>A | Splicing | <0.1% (ClinVar) | Exon skipping; loss of function |
Mutation functional classification
Loss of Function (LOF)
Missense mutations (e.g., R183W, P179L) and splice-site variants reduce or abolish PP2A catalytic activity, leading to unchecked phosphorylation of oncogenic substrates.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in PPP2CA; all known pathogenic variants result in loss or reduction of phosphatase activity.
Dominant Negative (DN)
De novo missense variants (e.g., E64K, D92N) act in a dominant-negative manner by disrupting holoenzyme assembly or substrate recognition, causing neurodevelopmental disorders.
View complete mutation data：
Gene Ontology (GO)
Pathways
• PI3K/AKT signaling pathway (Reactome: R-HSA-1257604)
• MAPK/ERK signaling pathway (Reactome: R-HSA-5673001)
• Wnt/β-catenin signaling pathway (Reactome: R-HSA-195721)
• Cell cycle
• mitotic (Reactome: R-HSA-69278)
• PP2A-mediated dephosphorylation (Reactome: R-HSA-8852276)
Protein Summary
PPP2CA encodes the 36 kDa catalytic subunit alpha of PP2A, a ubiquitously expressed serine/threonine phosphatase. The protein contains a conserved PP2Ac domain responsible for dephosphorylation of phosphoserine and phosphothreonine residues. It forms a heterotrimeric complex with scaffold (A) and regulatory (B) subunits, which dictate substrate specificity and subcellular localization. PPP2CA is essential for embryonic development and acts as a tumor suppressor by counteracting kinase-driven signaling. Post-translational modifications (e.g., phosphorylation at Tyr307, methylation at Leu309) modulate its activity and stability.
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