Protein phosphatase 1A (PPM1A)
The protein contains 382 amino acids for an estimated molecular weight of 42448 Da.
Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling. Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB. (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Cell cycle arrest
Cellular response to transforming growth factor beta stimulus
Dephosphorylation
Gene expression
Insulin receptor signaling pathway
N-terminal protein myristoylation
Negative regulation of BMP signaling pathway
Negative regulation of I-kappaB kinase/NF-kappaB signaling
Negative regulation of NF-kappaB import into nucleus
Negative regulation of NIK/NF-kappaB signaling
Negative regulation of SMAD protein complex assembly
Negative regulation of transcription by RNA polymerase II
Negative regulation of transforming growth factor beta receptor signaling pathway
Peptidyl-threonine dephosphorylation
Positive regulation of canonical Wnt signaling pathway
Positive regulation of I-kappaB kinase/NF-kappaB signaling
Positive regulation of protein export from nucleus
Positive regulation of transcription, DNA-templated
Positive regulation of Wnt signaling pathway
Protein dephosphorylation
Transcription initiation from RNA polymerase II promoter
Transcription, DNA-templated
Transforming growth factor beta receptor signaling pathway
Wnt signaling pathway
Cellular Component
Cytosol
Membrane
Neuron projection
Nucleoplasm
Nucleus
Plasma membrane
Voltage-gated calcium channel complex
Molecular Function
Calmodulin-dependent protein phosphatase activity
Magnesium ion binding
Magnesium-dependent protein serine/threonine phosphatase activity
Manganese ion binding
Obsolete signal transducer activity
Protein serine phosphatase activity
Protein serine/threonine phosphatase activity
Protein threonine phosphatase activity
R-SMAD binding
The reference OMIM entry for this protein is 606108
Protein phosphatase, magnesium/manganese-dependent, 1a; ppm1a
Protein phosphatase, magnesium-dependent, 1a
Protein phosphatase, magnesium-dependent, 1, alpha isoform
Protein phosphatase 2c, alpha isoform; pp2ca
Pp2c-alpha
DESCRIPTION
PPM1A is a serine/threonine protein phosphatase that is essential for regulating cellular stress responses in eukaryotes. For further background information on serine/threonine protein phosphatases, see 605119.CLONING
By screening a human teratocarcinoma cDNA library with rat Pp2c-alpha as the probe, Mann et al. (1992) cloned the human counterpart, PPM1A, which they called PP2C-alpha. The PPM1A cDNA encodes a predicted 382-amino acid peptide that shares 99.7% amino acid identity with rabbit Pp2c-alpha. In a genetic screen to identify protein phosphatases that negatively regulate the p38 (600289) and JNK (see 601158) stress-activated MAPK cascades, Takekawa et al. (1998) obtained a PP2C-alpha cDNA, which they initially called MC4, that encodes a 324-amino acid peptide. The authors hypothesized that MC4 is an alternative splicing product of PP2C-alpha. The 2 proteins, which they termed PP2C-alpha-1 (382 amino acids) and PP2C-alpha-2 (324 amino acids), differ at the C terminus. Northern blot analysis detected 2.8- and 4.4-kb transcripts, which correspond to PP2C-alpha-1 and PP2C-alpha-2, respectively. Both transcripts were expressed at high levels in heart, placenta, skeletal muscle, and pancreas, and the 4.4-kb transcript (PP2C-alpha-2) was detected in brain.MAPPING
Gross (2014) mapped the PPM1A gene to chromosome 14q23.1 based on an alignment of the PPM1A sequence (GenBank GENBANK AF070670) with the genomic sequence (GRCh38).GENE FUNCTION
Using immunohistochemical analysis, Das et al. (1996) detected PPM1A in both the cytoplasm and nucleus of mammalian cells, consistent with a role in dephosphorylating components of stress-activated pathways. By expressing PPM1A in mammalian cells, Takekawa et al. (1998) demonstrated that PPM1A inhibits the activation of the stress-responsive p38 and JNK MAPK cascades. Their in vivo and in vitro observations indicated that PPM1A dephosphorylates and inactivates MAPKKs (MKK6 (601254) and SEK1 (601335)) and a MAPK (p38) in the stress-responsive MAPK cascades. Using coimmunoprecipitation assays, the authors demonstrated that PPM1A directly interacts with p38. A key step in TGF-beta (TGFB1; 190180) signaling is ligand-induced phosphorylation of receptor-activated SMADs (see SMAD2; 601366). Using a functional genomic approach, Lin et al. (2006) identified human PPM1A as a SMAD phosphatase. PPM1A dephosphorylated and promoted nuclear export of TGF-beta-activated SMAD2 and SMAD3 (603109) in human cells. Ectopic expression of PPM1A abolished TGF-beta-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhanced TGF-beta signaling in human and other mammalian cells. In zebrafish, Smad-antagonizing activity of Ppm1a was observed during Nodal (601265)-dependent early embryogenesis. Lin et al. (2006) concluded that PPM1A plays a critical role in TGF-beta signaling through dephosphorylation of SMAD2 and SMAD3.BIOCHEMICAL FEATURES
Das et al. (1996) determined the crystal structure of PPM1A, which they called PP2C. The structure revealed a novel protein fold with a catalytic domain composed of a central beta sandwich that binds 2 manganese ions, which is surrounded by alpha helices. The authors stated that the protein architecture and deduced catalytic mechanism are similar to the PP1, PP2A, and PP2B family of protein ser/thr phosphatases. ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606108 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed