Alternative titles; symbols
HGNC Approved Gene Symbol: PPP5C
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:46,347,087-46,390,975 (from NCBI)
A variety of biologic processes, such as cell signaling, transcription, and mitosis, are regulated by reversible protein phosphorylation at serine and threonine residues. The serine/threonine kinases are responsible for phosphorylation and the phosphatases are required for dephosphorylation. A number of protein serine/threonine phosphatases are known and molecular characterization shows that they fall into distinct groups. One family includes the PP1 (see PPP1A, 176875), PP2A, and PP2B (see PPP2B, 114105) genes and their relatives. Chen et al. (1994) described a protein serine/threonine phosphatase, which they designated PP5, that shares similarity to the yeast gene PPT1. The PP5 cDNA was isolated by screening a human teratocarcinoma cDNA library at low stringency with a PP2B probe. By Northern blotting they observed a 2.3-kb mRNA in all tissues they examined. The predicted PP5 protein shares about 35 to 40% identity with other members of the superfamily and the N-terminal domain contains tetratricopeptide-like repeats found in several nuclear regulatory proteins. Recombinant PP5 was able to dephosphorylate serine residues and was shown to be sensitive to the tumor promoter okadaic acid. Antibodies showed that the protein is predominantly found in the nucleus.
Yong et al. (1995) reported the isolation of a cDNA from a human fetal brain library by exon amplification from a cosmid contig mapping to a glioma candidate region on chromosome 19q13.3. A nearly full-length cDNA was then obtained that was identical to PPP5C except for 3 additional nucleotides. Xu et al. (1996) cloned the entire coding sequence of the PP5 gene from a human fetal brain cDNA library using a probe generated by a PCR-based cloning approach. The PP5 mRNA was detected in all human tissues examined.
Gentile et al. (2006) identified Pp5 as an effector of Rac (see 602048) GTPase signaling in a rat pituitary cell line. Okadaic acid, a microbial toxin, blocked channel stimulation by thyroid hormone and by Rac, and signaling was restored by expression of a toxin-insensitive Pp5 mutant. Pp5 contains an N-terminal regulatory domain with 3 tetratricopeptide (TRP) repeats that inhibit its activity. Expression of the TRP domain of Pp5 blocked channel stimulation by thyroid hormone, and mutation of the TRP at 2 predicted contact points with Rac-GTP prevented its inhibitory activity.
Using yeast 2-hybrid and protein pull-down assays, Kono et al. (2002) found that mouse G5pr (PPP2R3C; 615902) interacted with Ganp DNA primase (MCM3AP; 603294) and with 2 types of catalytic protein phosphatases, Pp2ca (PPP2CA; 176915) and Pp5. G5pr did not interact with Pp2ca and Pp5 simultaneously. Proteins that precipitated with G5pr from mouse spleen lysates showed phosphatase activity that was sensitive to okadaic acid, an inhibitor of both Pp2ca and Pp5. In vitro-phosphorylated Mcm3 (602693) was dephosphorylated by the G5pr complex in the absence of okadaic acid, and dephosphorylation was enhanced by arachidonic acid, a Pp5 activator.
Katayama et al. (2014) found that PP5 alone showed little to no phosphatase activity against serine-phosphorylated CRAF (RAF1; 164760), but that it clearly dephosphorylated CRAF in the presence of PPP2R3C. PPP2R3C also stimulated PP5-dependent dephosphorylation of serine-phosphorylated P-glycoprotein (ABCB1; 171050). Knockdown of PP5/PPP2R3C increased P-glycoprotein expression and lowered cell sensitivity to chemotherapeutic agents.
By fluorescence in situ hybridization, Xu et al. (1996) mapped the PP5 gene to chromosome 19q13.3.
For discussion of a possible association between variation in the PPP5C gene and developmental and epileptic encephalopathy, see 600658.0001.
Yong et al. (2007) generated PP5 knockout mice and isolated mouse embryonic fibroblasts (MEF) cells from PP5-deficient and littermate control embryos. PP5-deficient MEF cells displayed a defect in G2/M DNA damage when subjected to ionizing radiation due to reduced ATM (607585)-mediated signaling, suggesting involvement of PP5 in the DNA damage checkpoint pathway.
Wang et al. (2018) also generated PP5 knockout mice. Homozygous mice displayed deficiencies in cartilage formation in vertebrae, limbs, and feet and had wider growth plates, more chondrocytes, and higher expression of cartilage-specific genes than wildtype animals. The knockout mice showed reduced body weight and shorter femur length with increased femur weight due to additional trabecular bone mass and improved cortical thickness. Expression of aggrecan (ACAN; 155760) and RUNX1 (151385), both of which are required for cartilage development, was also increased.
Fielder et al. (2022) showed that a C. elegans model harboring an A48T mutation in the pph5 gene, corresponding to the human PPP5C mutation A47T (605065.0001), on an mec15 mutant background, demonstrated abnormal neurite growth and abnormal GABA signaling compared to wildtype pph5 on an mec15 mutant background.
This variant is classified as a variant of unknown significance because its contribution to developmental and epileptic encephalopathy (see DEE1, 308350) has not been confirmed.
In a 6-year-old girl with developmental and epileptic encephalopathy, Fielder et al. (2022) identified a de novo heterozygous c.139G-A transition (c.139G-A, NM_006247.3) in the PPP5C gene, resulting in an ala47-to-thr (A47T) substitution. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). The patient had epilepsy, nystagmus, congenital microcephaly, and developmental delay. A brain MRI at 4 years of age showed reduced cerebral white matter volume. Seizures, which began at 12 to 16 months of age, were refractory to treatment.
Chen, M. X., McPartlin, A. E., Brown, L., Chen, Y. H., Barker, H. M., Cohen, P. T. W. A novel human protein serine/threonine phosphatase, which possesses four tetratricopeptide repeat motifs and localizes to the nucleus. EMBO J. 13: 4278-4290, 1994. [PubMed: 7925273] [Full Text: https://doi.org/10.1002/j.1460-2075.1994.tb06748.x]
Fielder, S. M., Rosenfeld, J. A., Burrage, L. C., Emrick, L., Lalani, S., Attali, R., Bembenek, J. N., Hoang, H., Baldridge, D., Silverman, G. A., Undiagnosed Diseases Network, Schedl, T., Pak, S. C. Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay. Molec. Genet. Metab. 136: 65-73, 2022. [PubMed: 35361529] [Full Text: https://doi.org/10.1016/j.ymgme.2022.03.007]
Gentile, S., Darden, T., Erxleben, C., Romeo, C., Russo, A., Martin, N., Rossie, S., Armstrong, D. L. Rac GTPase signaling through the PP5 protein phosphatase. Proc. Nat. Acad. Sci. 103: 5202-5206, 2006. [PubMed: 16549782] [Full Text: https://doi.org/10.1073/pnas.0600080103]
Katayama, K., Yamaguchi, M., Noguchi, K., Sugimoto, Y. Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function. Cancer Lett. 345: 124-131, 2014. [PubMed: 24333728] [Full Text: https://doi.org/10.1016/j.canlet.2013.12.007]
Kono, Y., Maeda, K., Kuwahara, K., Yamamoto, H., Miyamoto, E., Yonezawa, K., Takagi, K., Sakaguchi, N. MCM3-binding GANP DNA-primase is associated with a novel phosphatase component G5PR. Genes Cells 7: 821-834, 2002. [PubMed: 12167160] [Full Text: https://doi.org/10.1046/j.1365-2443.2002.00562.x]
Wang, J., Cao, Y., Qiu, B., Du, J., Wang, T., Wang, C., Deng, R., Shi, X., Gao, K., Xie, Z., Yong, W. Ablation of protein phosphatase 5 (PP5) leads to enhanced both bone and cartilage development in mice. Cell Death Dis. 9: 214, 2018. [PubMed: 29434189] [Full Text: https://doi.org/10.1038/s41419-017-0254-6]
Xu, X., Lagercrantz, J., Zickert, P., Bajalica-Lagercrantz, S., Zetterberg, A. Chromosomal localization and 5-prime sequence of the human protein serine/threonine phosphatase 5-prime gene. Biochem. Biophys. Res. Commun. 218: 514-517, 1996. [PubMed: 8561788] [Full Text: https://doi.org/10.1006/bbrc.1996.0092]
Yong, W., Bao, S., Chen, H., Li, D., Sanchez, E. R., Shou, W. Mice lacking protein phosphatase 5 are defective in ataxia telangiectasia mutated (ATM)-mediated cell cycle arrest. J. Biol. Chem. 282: 14690-14694, 2007. [PubMed: 17376776] [Full Text: https://doi.org/10.1074/jbc.C700019200]
Yong, W. H., Ueki, K., Chou, D., Reeves, S. A., von Deimling, A., Gusella, J. F., Mohrenweiser, H. W., Buckler, A. J., Louis, D. N. Cloning of a highly conserved human protein serine-threonine phosphatase gene from the glioma candidate region on chromosome 19q13.3. Genomics 29: 533-536, 1995. [PubMed: 8666404] [Full Text: https://doi.org/10.1006/geno.1995.9972]