Alternative titles; symbols
HGNC Approved Gene Symbol: PPP1CA
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38) : 11:67,398,183-67,401,858 (from NCBI)
Protein phosphorylation, a crucial posttranslational modification that controls many diverse cellular functions, is dependent on the opposing actions of protein kinases and protein phosphatases. Protein phosphatase-1 (PP1) is 1 of 4 major protein phosphatases identified in the cytosol of eukaryotic cells that are responsible for the dephosphorylation of serine and threonine residues in proteins. Although all 4 protein phosphatases have overlapping substrate specificities in vitro, they can be distinguished by the use of inhibitor proteins and by their dependence on metal ions. PP1 is inhibited by nanomolar concentrations of 2 thermostable proteins, inhibitor-1 (PPP1R1A; 613246) and inhibitor-2 (PPP1R2; 601792), whereas the other 3 phosphatases (see PPP2CA; 176915) are unaffected by these inhibitors. PPP1CA encodes a catalytic subunit of PP1 that forms heterodimers with various PP1 regulatory subunits (e.g., PPP1R3A; 600917). These regulatory subunits target PP1 to particular subcellular locations and selectively enhance its activity toward certain substrates (Cohen and Cohen, 1989).
Barker et al. (1990) isolated a cDNA encoding 1 isoform (PP1-alpha) of the catalytic subunit of human protein phosphatase-1.
Using 2 regions conserved within PP1 genes, Song et al. (1993) amplified a partial PPP1CA sequence by PCR, and they screened a cDNA library using this product to obtain a full-length clone. The deduced 330-amino acid protein shows complete concordance with the rabbit protein. Northern blot analysis revealed 1.6-kb transcript.
Using fluorescence imaging of HeLa cells, Trinkle-Mulcahy et al. (2006) showed that both PP1-alpha and -gamma (PPP1CC; 176914) localized in the cytoplasm and nucleus throughout G1, S, and G2 phases. However, nuclear PP1-alpha was mainly in a diffuse pool and largely excluded from nucleoli, whereas nuclear PP1-gamma showed strong accumulation within nucleoli. PP1-alpha and -gamma also differed in their dynamic distribution during cell division. Both PP1-alpha and -gamma localized to kinetochores in metaphase, but PP1-alpha appeared to be predominantly excluded from other chromatin regions at this stage, in contrast with PP1-gamma. In addition, accumulation of PP1-gamma on chromatin increased dramatically at anaphase.
Genoux et al. (2002) demonstrated that PP1 determined the efficacy of learning and memory by limiting acquisition and favoring memory decline. When PP1 is genetically inhibited during learning, short intervals between training episodes are sufficient for optimal performance. Enhanced learning correlates with increased phosphorylation of CREB (123810), of CAMKII (114078), and of the GLUR1 subunit of the AMPA receptor (138248); it also correlates with CREB-dependent gene expression that, in control mice, occurs only with widely distributed training. Inhibition to PP1 prolongs memory when induced after learning, suggesting that PP1 also promotes forgetting. Genoux et al. (2002) suggested that this property may account for age-related cognitive decay, as old mutant mice had preserved memory. They concluded that their findings emphasized the physiologic importance of PP1 as a suppressor of learning and memory, and as a potential mediator of cognitive decline during aging.
Danial et al. (2003) undertook a proteomic analysis to assess whether BAD (603167) might participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A (see 176911) and PP1 catalytic units, WAVE1 (605035) as an A kinase-anchoring protein, and glucokinase (138079). Using mitochondria from hepatocytes of Bad-deficient mice, Danial et al. (2003) demonstrated that BAD is required to assemble the complex, the lack of which results in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death.
In CT26 mouse colon cancer cells, Obeid et al. (2007) demonstrated that anthracyclins induced immunogenic cell death by way of a rapid, preapoptotic translocation of calreticulin (CALR; 109091) to the cell surface. Anthracyclin-induced Calr translocation was mimicked by inhibition of the Ppp1ca/Gadd34 (PPP1R15A; 611048) complex. Administration of recombinant Calr or inhibitors of Ppp1ca/Gadd34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C and enhanced their antitumor effects in vivo.
Novoyatleva et al. (2008) identified a consensus PP1-binding motif, RVxF, in the RNA recognition motifs of several splicing factors, including TRA2-beta (SFRS10; 602719), SF2/ASF (SFRS1; 600812), and SRp30c (SFRS9; 601943). PP1 bound directly to this motif in TRA2-beta and dephosphorylated the protein, altering its interaction with other proteins. Reducing PP1 activity promoted usage of numerous alternative exons, including the inclusion of the SMN2 (601627) exon 7 in mice expressing the human gene. Novoyatleva et al. (2008) concluded that PP1 has a role in splice site selection.
By immunoprecipitation and mass spectrometric analysis of PP1 complexes in HEK293 cells, Lee et al. (2010) identified a complex containing PNUTS (PPP1R10; 603771), TOX4 (614032), WDR82 (611059), and any 1 of the 3 PP1 catalytic subunits, PP1-alpha, PP1-beta (PPP1CB; 600590), or PP1-gamma (PPP1CC; 176914). The complex, which they called PTW/PP1, had an apparent molecular mass of about 200 kD, suggesting that it contains 1 molecule of each subunit. Mutation analysis revealed that human PP1-alpha interacted with the RVxF motif of mouse Pnuts. PP1-alpha did not interact directly with human TOX4 and WDR82. The PTW/PP1 complex efficiently dephosphorylated the isolated C-terminal domain of the large subunit of mouse RNA polymerase II (POLR2A; 180660) in vitro. The PTW/PP1 complex was stable throughout the cell cycle in HEK293 cells, but its association with chromatin was regulated. PTW/PP1 associated with chromatin during interphase, was excluded from condensed chromosomes during early mitosis, and was reloaded onto chromosomes at late telophase.
Rodrigues et al. (2015) studied division in proliferating Drosophila and human cells and demonstrated the existence of a signaling pathway that triggers the relaxation of the polar cell cortex at mid anaphase. This is independent of furrow formation, centrosomes, and microtubules and instead depends on PP1 phosphatase and its regulatory subunit Sds22 (602877). As separating chromosomes move towards the polar cortex at mid anaphase, kinetochore-localized PP1-Sds22 helps to break cortical symmetry by inducing the dephosphorylation and inactivation of ezrin (123900)/radixin (179410)/moesin (309845) proteins at cell poles. This promotes local softening of the cortex, facilitating anaphase elongation and orderly cell division. Rodrigues et al. (2015) concluded that their study identified a conserved kinetochore-based phosphatase signal and substrate, which function together to link anaphase chromosome movements to cortical polarization, thereby coupling chromosome segregation to cell division.
Crystal Structure
Terrak et al. (2004) demonstrated the crystal structure at 2.7-angstrom resolution of the complex between PP1 and a 34-kD N-terminal domain of the myosin phosphatase targeting subunit MYPT1 (602021). MYPT1 is the protein that regulates PP1 function in smooth muscle relaxation. Structural elements amino- and carboxy-terminal to the RVXF motif of MYPT1 are positioned in a way that leads to a pronounced reshaping of the catalytic cleft of PP1, contributing to the increased myosin specificity of this complex. Terrak et al. (2004) concluded that the structure has general implications for the control of PP1 activity by other regulatory subunits.
Barker et al. (1990) mapped the PPP1A gene to chromosome 11q13 by Southern analysis of somatic cell hybrids and by in situ hybridization. Translocations involving breakpoints at 11q13 have been observed in lymphomas, chronic lymphocytic leukemia of the B-cell type (see 151400), and multiple myeloma. Other oncogenes or suppressors mapping to 11q13 include HST (164980), INT2 (164950), SEA (165110), and ST3 (191181).
Richard et al. (1991) described a high-resolution radiation hybrid map of 11q12-q13, which placed the PPP1A locus at the extreme end of a cluster of more than 12 genes with C1NH (606860) at the other end and with GST3 (134660) as its closest neighbor in the linear array. Using fluorescence in situ hybridization, Saadat et al. (1995) mapped PPP1CA to human 11q13, rat 1q43, and mouse 7E3-F2. The results indicated that PPP1CA is a member of a group of genes showing homology of synteny.
Carr et al. (2002) noted that increased PP1 activity has been observed in end-stage human heart failure. They developed a mouse model for cardiac tissue-specific overexpression of PP1 by introducing PPP1CA inserted downstream of the mouse alpha-myosin heavy chain promoter. Overexpression of PP1 was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Knockout of Ipp1 was associated with moderate increases in PP1 activity and impaired beta-adrenergic contractile responses. Expression of constitutively active IPP1 in failing human myocytes in culture was associated with rescue of beta-adrenergic responsiveness.
Barker, H. M., Jones, T. A., da Cruz e Silva, E. F., Spurr, N. K., Sheer, D., Cohen, P. T. W. Localization of the gene encoding a type I protein phosphatase catalytic subunit to human chromosome band 11q13. Genomics 7: 159-166, 1990. [PubMed: 2161401] [Full Text: https://doi.org/10.1016/0888-7543(90)90536-4]
Carr, A. N., Schmidt, A. G., Suzuki, Y., del Monte, F., Sato, Y., Lanner, C., Breeden, K., Jing, S.-L., Allen, P. B., Greengard, P., Yatani, A., Hoit, B. D., Grupp, I. L., Hajjar, R. J., DePaoli-Roach, A. A., Kranias, E. G. Type 1 phosphatase, a negative regulator of cardiac function. Molec. Cell. Biol. 22: 4124-4135, 2002. [PubMed: 12024026] [Full Text: https://doi.org/10.1128/MCB.22.12.4124-4135.2002]
Cohen, P., Cohen, P. T. W. Protein phosphatases come of age. J. Biol. Chem. 264: 21435-21438, 1989. [PubMed: 2557326]
Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424: 952-956, 2003. [PubMed: 12931191] [Full Text: https://doi.org/10.1038/nature01825]
Genoux, D., Haditsch, U., Knobloch, M., Michalon, A., Storm, D., Mansuy, I. M. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418: 970-975, 2002. [PubMed: 12198546] [Full Text: https://doi.org/10.1038/nature00928]
Lee, J.-H., You, J., Dobrota, E., Skalnik, D. G. Identification and characterization of a novel human PP1 phosphatase complex. J. Biol. Chem. 285: 24466-24476, 2010. [PubMed: 20516061] [Full Text: https://doi.org/10.1074/jbc.M110.109801]
Novoyatleva, T., Heinrich, B., Tang, Y., Benderska, N., Butchbach, M. E. R., Lorson, C. L., Lorson, M. A., Ben-Dov, C., Fehlbaum, P., Bracco, L., Burghes, A. H. M., Bollen, M., Stamm, S. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Hum. Molec. Genet. 17: 52-79, 2008. [PubMed: 17913700] [Full Text: https://doi.org/10.1093/hmg/ddm284]
Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J.-L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Metivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., Kroemer, G. Calreticulin exposure dictates immunogenicity of cancer cell death. Nature Med. 13: 54-61, 2007. [PubMed: 17187072] [Full Text: https://doi.org/10.1038/nm1523]
Richard, C. W., Withers, D. A., Meeker, T. C., Myers, R. M. A radiation hybrid map of the proximal long arm of human chromosome 11 containing the MEN-1 and bcl-1 disease locus. (Abstract) Cytogenet. Cell Genet. 58: 1970 only, 1991.
Rodrigues, N. T. L., Lekomtsev, S., Jananji, S., Kriston-Vizi, J., Hickson, G. R. X., Baum, B. Kinetochore-localized PP1-Sds22 couples chromosome segregation to polar relaxation. Nature 524: 489-492, 2015. [PubMed: 26168397] [Full Text: https://doi.org/10.1038/nature14496]
Saadat, M., Mizuno, Y., Kikuchi, K., Yoshida, M. C. Comparative mapping of the gene encoding the catalytic subunit of protein phosphatase type 1-alpha (PPP1CA) to human, rat, and mouse chromosomes. Cytogenet. Cell Genet. 70: 55-57, 1995. [PubMed: 7736790] [Full Text: https://doi.org/10.1159/000133991]
Song, Q., Khanna, K. K., Lu, H., Lavin, M. F. Cloning and characterization of a human protein phosphatase 1-encoding cDNA. Gene 129: 291-295, 1993. [PubMed: 8392016] [Full Text: https://doi.org/10.1016/0378-1119(93)90282-8]
Terrak, M., Kerff, F., Langsetmo, K., Tao, T., Dominguez, R. Structural basis of protein phosphatase 1 regulation. Nature 429: 780-784, 2004. [PubMed: 15164081] [Full Text: https://doi.org/10.1038/nature02582]
Trinkle-Mulcahy, L., Andersen, J., Lam, Y. W., Moorhead, G., Mann, M., Lamond, A. I. Repo-Man recruits PP1-gamma to chromatin and is essential for cell viability. J. Cell Biol. 172: 679-692, 2006. [PubMed: 16492807] [Full Text: https://doi.org/10.1083/jcb.200508154]