Molecule Information

General Information of the Molecule (ID: Mol04387)

• Name: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: PPP1CA
• Gene ID: 5499
• Sequence:
  MSDSEKLNLDSIIGRLLEVQGSRPGKNVQLTENEIRGLCLKSREIFLSQPILLELEAPLK
  ICGDIHGQYYDLLRLFEYGGFPPESNYLFLGDYVDRGKQSLETICLLLAYKIKYPENFF
  L LRGNHECASINRIYGFYDECKRRYNIKLWKTFTDCFNCLPIAAIVDEKIFCCHGGLSP
  DL QSMEQIRRIMRPTDVPDQGLLCDLLWSDPDKDVQGWGENDRGVSFTFGAEVVAKFLH
  KHD LDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGAMMSVDETLMCSFQIL
  KPAD KNKGKYGQFSGLNPGGRPITPPRNSAKAKK
• Function: Protein phosphatase that associates with over 200 regulatoryproteins to form highly specific holoenzymes which dephosphorylatehundreds of biological targets . Protein phosphatase 1 isessential for cell division, transcription elongation, and participatesin the regulation of glycogen metabolism, muscle contractility andprotein synthesis . Involved inregulation of ionic conductances and long-term synaptic plasticity. Mayplay an important role in dephosphorylating substrates such as thepostsynaptic density-associated Ca/calmodulin dependent proteinkinase II. Catalytic component of the PNUTS-PP1 protein phosphatasecomplex, a protein phosphatase 1 complex that promotes RNApolymerase II transcription pause-release, allowing transcriptionelongation: the PNUTS-PP1 complex mediates the release of RNApolymerase II from promoter-proximal region of genes by catalyzingdephosphorylation of proteins involved in transcription, such as AFF4,CDK9, MEPCE, INTS12, NCBP1, POLR2M/GDOWN1 and SUPT6H . The PNUTS-PP1 complex also regulates transcriptiontermination by mediating dephosphorylation of SUPT5H in terminationzones downstream of poly sites, thereby promoting deceleration ofRNA polymerase II transcription . PNUTS-PP1 complex isalso involved in the response to replication stress by mediatingdephosphorylation of POLR2A at 'Ser-5' of the CTD, promoting RNApolymerase II degradation . PNUTS-PP1 also plays arole in the control of chromatin structure and cell cycle progressionduring the transition from mitosis into interphase .Regulates NEK2 function in terms of kinase activity and centrosomenumber and splitting, both in the presence and absence of radiation-induced DNA damage . Regulator of neural tube andoptic fissure closure, and enteric neural crest cell migrationduring development . In balance with CSNK1D and CSNK1E,determines the circadian period length, through the regulation of thespeed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 inregulatory T-cells from patients with rheumatoid arthritis,thereby inactivating FOXP3 and rendering Treg cells functionallydefective . Dephosphorylates CENPA .Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociationof ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy. Together with PPP1CC ,dephosphorylates IFIH1/MDA5 and RIG-I leading to their activation and afunctional innate immune response . Core component ofthe SHOC2-MRAS-PP1c holophosphatase complex that regulates theMAPK pathway activation . The SMP complex specificallydephosphorylates the inhibitory phosphorylation at 'Ser-259' of RAF1kinase, 'Ser-365' of BRAF kinase and 'Ser-214' of ARAF kinase,stimulating their kinase activities . The SMP complex enhances thedephosphorylation activity and substrate specificity of PP1c. {ECO:0000250|UniProtKB:P62137,ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:20516061,ECO:0000269|PubMed:21712997, ECO:0000269|PubMed:23396208,ECO:0000269|PubMed:23499489, ECO:0000269|PubMed:25556658,ECO:0000269|PubMed:26083323, ECO:0000269|PubMed:28216226,ECO:0000269|PubMed:30158517, ECO:0000269|PubMed:31677974,ECO:0000269|PubMed:33264625, ECO:0000269|PubMed:35768504,ECO:0000269|PubMed:35830882, ECO:0000269|PubMed:35831509,ECO:0000269|PubMed:36175670, ECO:0000269|PubMed:39603239,ECO:0000269|PubMed:39603240}.; Necessary for alphaviruses replication.{ECO:0000269|PubMed:29769351}.
• Uniprot ID: PP1A_HUMAN
• Ensembl ID: ENSG0000017253116
• HGNC ID: HGNC:9281

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Abiraterone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Castration-resistant prostate cancer [ICD-11: 2C82.0] [1]

• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Abiraterone
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 22Rv-1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: qRT-PCR; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: In conclusion, we reveals a novel regulator PPP1CA driving abiraterone resistance. The natural product nodularin-R ameliorates abiraterone resistance by inhibiting PPP1CA. The combination of nodularin-R and abiraterone exerts synergistic anti-CRPC effects.

References

• Ref 1: Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition. J Cell Mol Med. 2024 Nov;28(22):e70210.