PPP6C: Protein Phosphatase 6 Catalytic Subunit
A key regulator of cell cycle progression and DNA damage response, frequently mutated in melanoma and other cancers.
Gene Information Card
| Symbol | PPP6C |
|---|---|
| Full Name | Protein Phosphatase 6 Catalytic Subunit |
| Gene Type | Protein coding |
| Chromosomal Location | 9q33.3 |
| NCBI Gene ID | 5537 ncbi.nlm.nih.gov/gene/5537 |
| Ensembl ID | ENSG00000108055 |
| UniProt ID | O00743 |
| OMIM ID | 612725 |
| HGNC ID | 9320 |
| Aliases | PP6C, PPP6, serine/threonine-protein phosphatase 6 catalytic subunit |
Description
PPP6C encodes the catalytic subunit of protein phosphatase 6 (PP6), a serine/threonine phosphatase involved in cell cycle regulation, DNA damage response, and NF-kappaB signaling. The PP6 holoenzyme dephosphorylates key substrates including Aurora kinase A, DNA-PKcs, and IKKbeta. PPP6C is recurrently mutated in melanoma and other cancers, with hotspot mutations affecting its phosphatase activity and substrate specificity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Melanoma | Recurrent somatic mutations (e.g., R264C, R264H) impair PP6 catalytic activity, leading to dysregulated Aurora A and DNA damage signaling, promoting tumorigenesis. | COSMIC, ClinVar, PMID: 25261994 |
| Breast cancer | PPP6C loss or mutation contributes to genomic instability and altered cell cycle progression. | COSMIC, PMID: 23583978 |
| Lung cancer | Somatic mutations and copy number alterations in PPP6C observed in non-small cell lung cancer. | COSMIC, PMID: 22980975 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 18.5 | High |
| Brain | 12.3 | Medium |
| Heart | 10.1 | Medium |
| Liver | 8.7 | Medium |
| Lung | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 15.2 | Embryonic kidney, high expression |
| HeLa | 12.8 | Cervical carcinoma, moderate |
| A375 | 9.5 | Melanoma cell line, moderate |
| MCF7 | 8.1 | Breast cancer, moderate |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| R264C | Missense | Recurrent in melanoma (~5-10%) | Reduces phosphatase activity; alters substrate binding |
| R264H | Missense | Recurrent in melanoma | Similar to R264C; loss-of-function |
| E197K | Missense | Rare | Impaired catalytic activity |
| L350R | Missense | Rare | Disrupts PP6 complex assembly |
Mutation functional classification
Loss of Function (LOF)
R264C, R264H, E197K, L350R reduce or abolish PP6 catalytic activity, impairing dephosphorylation of Aurora A and DNA-PKcs.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported.
Dominant Negative (DN)
R264C and R264H may act as dominant-negative by competing with wild-type PPP6C for regulatory subunit binding.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Cell Cycle
• Mitotic (Reactome: R-HSA-69278)
• DNA Double-Strand Break Repair (Reactome: R-HSA-5693532)
• NF-kappaB Signaling (KEGG: hsa04064)
• Aurora A Signaling (Reactome: R-HSA-8852276)
Protein Summary
PPP6C is a 35 kDa catalytic subunit of protein phosphatase 6, a member of the PPP family of serine/threonine phosphatases. The protein contains a conserved phosphatase domain and interacts with regulatory subunits (e.g., PP6R1, PP6R2, PP6R3) to form active holoenzymes. PPP6C dephosphorylates Aurora A at T288, DNA-PKcs at S2056, and IKKbeta at S177/181, thereby regulating mitotic entry, DNA repair, and inflammatory signaling. Mutations in the catalytic domain, particularly at arginine 264, are oncogenic drivers in melanoma.
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