Alternative titles; symbols
HGNC Approved Gene Symbol: PPM1L
Cytogenetic location: 3q25.33-q26.1 Genomic coordinates (GRCh38): 3:160,756,231-161,078,902 (from NCBI)
PPM1L, or PP2CE, belongs to the PP2C group of serine/threonine phosphatases, which are distinguished from other phosphatases by their structure, absolute requirement for Mg(2+) or Mn(2+), and insensitivity to okadaic acid. PP2Cs regulate stress-activated protein kinase (SAPK; see 601158) signaling cascades that respond to extracellular stimuli (Jin et al., 2004).
Li et al. (2003) cloned mouse Pp2ce, which encodes a deduced 303-amino acid protein. Northern blot analysis detected strong expression of a 5.9-kb transcript in brain, with weaker expression in heart. A 2.2-kb transcript was detected in testis only. PCR analysis also showed Pp2ce expression in liver, lung, and skeletal muscle.
By sequence analysis of a fetal brain cDNA library, Jin et al. (2004) cloned human PP2CE. The deduced 360-amino acid protein has a calculated molecular mass of 41 kD. Like other PP2Cs, PP2CE contains a PP2C catalytic domain, unique N- and C-terminal domains, and several highly conserved residues for Mg(2+)/Mn(2+) binding. Human PP2CE shares 99% identity with the mouse and rat Pp2ce proteins, which also contain 360 amino acids. RT-PCR detected highest PP2CE expression in human heart, placenta, lung, liver, kidney, and pancreas, with lower expression in colon, leukocytes, testis, and brain. Jin et al. (2004) noted that the expression pattern for human PP2CE is different from that found in mouse.
Li et al. (2003) found that recombinant mouse Pp2ce exhibited substantial Mg(2+)- or Mn(2+)-dependent protein phosphatase activity that was insensitive to okadaic acid. Ectopic expression of Pp2ce in HEK293 human embryonic kidney cells inhibited IL1 (see 147760)- and TAK1 (MAP3K7; 602614)-induced activation of the MKK4 (MAP2K4; 601335)/JNK (601158) or MKK3 (MAP2K3; 602315)/p38 (MAPK14; 600289) signaling pathways. Pp2ce dephosphorylated TAK1 in vitro. Coimmunoprecipitation experiments revealed that Pp2ce associated stably with TAK1 and attenuated binding of TAK1 to MKK4 or MKK6 (MAP2K6; 601254). A phosphatase-negative Pp2ce mutant acted as a dominant-negative form and enhanced both association of TAK1 with MKK4 or MKK6 and TAK1-induced activation of an AP1 (165160) reporter gene. The association between Pp2ce and TAK1 was transiently suppressed by IL1 treatment. Li et al. (2003) concluded that, in the absence of IL1 signaling, PP2CE inactivates the TAK1 signaling pathway by associating with and dephosphorylating TAK1.
Saito et al. (2007) found that expression of mouse Pp2ce in HEK293 cells inhibited Ask1 (MAP3K5; 602448)-induced activation of an AP1 reporter gene. Conversely, a dominant-negative Pp2ce mutant enhanced AP1 activity. Mouse Pp2ce and Ask1 interacted in HEK293 cells under nonstressed conditions, and Pp2ce inactivated Ask1 by decreasing thr845 phosphorylation in the cell system and also in vitro. The association of Pp2ce and Ask1 was also observed in mouse brain extracts. In contrast with PP5 (PPP5C; 600658), Pp2ce transiently dissociated from Ask1 within cells upon peroxide treatment. Saito et al. (2007) concluded that PP2CE maintains ASK1 in an inactive state by dephosphorylation in quiescent cells.
Jin et al. (2004) determined that the PP2CE gene contains 4 exons and spans 315 kb.
By genomic sequence analysis, Jin et al. (2004) mapped the PP2CE gene to chromosome 3q26.1.
Chen et al. (2008) studied weight, fat mass, insulin and glucose levels, blood pressure, and other biochemical measures in blood in Ppm1l knockout and wildtype littermate control mice. The growth curves of the knockout mice were significantly different from those of wildtype controls; at the final weight measurement, knockout mice weighed 19.3% more than wildtype mice. Ppm1l-null mice also exhibited increased fat mass compared to wildtype controls, with an overall 46.7% increase in fat mass at 20 weeks of age. At 21 weeks of age an oral glucose tolerance test revealed baseline plasma glucose levels to be 11.5% higher in Ppm1l-null mice relative to wildtype mice. Male knockout mice demonstrated an improved glucose tolerance, with 33% decrease in area under the curve relative to wildtype male mice. In contrast, although glucose levels in females at the 60-, 90-, and 180-minute time points were significantly increased, the difference in area under the curve was not statistically significant. Ppm1l-null male mice also had a significant decrease in free fatty acids, and blood pressure was higher in Ppm1l-null mice.
Chen, Y., Zhu, J., Lum, P. Y., Yang, X., Pinto, S., MacNeil, D. J., Zhang, C., Lamb, J., Edwards, S., Sieberts, S. K., Leonardson, A., Castellini, L. W., and 10 others. Variations in DNA elucidate molecular networks that cause disease. Nature 452: 429-435, 2008. [PubMed: 18344982] [Full Text: https://doi.org/10.1038/nature06757]
Jin, F., Ji, C., Liu, L., Dai, J., Gu, S., Sun, X., Xie, Y., Mao, Y. Molecular cloning and characterization of a novel human protein phosphatase 2C cDNA (PP2C epsilon). Molec. Biol. Rep. 31: 197-202, 2004. [PubMed: 15560375] [Full Text: https://doi.org/10.1023/b:mole.0000043624.96006.eb]
Li, M. G., Katsura, K., Nomiyama, H., Komaki, K., Ninomiya-Tsuji, J., Matsumoto, K., Kobayashi, T., Tamura, S. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2C-epsilon). J. Biol. Chem. 278: 12013-12021, 2003. [PubMed: 12556533] [Full Text: https://doi.org/10.1074/jbc.M211474200]
Saito, J., Toriumi, S., Awano, K., Ichijo, H., Sasaki, K., Kobayashi, T., Tamura, S. Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase 2C-epsilon. Biochem. J. 405: 591-596, 2007. [PubMed: 17456047] [Full Text: https://doi.org/10.1042/BJ20070231]