Phosphatase Subfamily PPM1L

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM: Family PPM: Subfamily PPM1L (PP2Cε, PP2Ce)

Evolution

PPM1L is found in most chordate and arthropod genomes, indicating that it emerged in bilateria and was lost in nematodes. PPM1L is most closely related to PPM1K, a mitochondrial phosphatase.

Domain

PPM1L has an N-terminal transmembrane (TM) region, followed by PPM phosphatase domain. The TM (residues (26-45) of Human PPM1L has been experimentally validated, and the phosphatase domain shown to be on the cytoplasmic side of the endoplasmic reticulum membrane [1]; the TMs of sea urchin and Drosophila PPM1Ls are predicted by sequence analysis [TMHMM].

Functions

Human PPM1L is widely expressed in different tissues. Although it is most abundant in heart, placenta, lung, liver, kidney and pancreas as shown by RT-PCR [2], RNA-seq data from [GTEx] showed different tissue distribution.

Human PPM1L has the following characterized substrates:

• TAK1. Human PPM1L associated with, dephosphorylated and inactivated TAK1 in vitro [3]. TAK1 can be also dephosphorylated by another PPM, PPM1B, and associates with another PPM, the pseudophosphatase TAB1. TAK1 emerged in holozoa.
• ASK1 (at Thr-845). Human PPM1L dephosphorylated ASK1 in vitro and associated with ASK1 in mouse brain extracts [4]. ASK1 is also dephosphorylated by PP5, a member of the [[Phosphatase_Subfamily_PPP5C|PPP5C] subfamily of PPP phosphatases. The difference between PPM1L and PP5 is upon H2O2 exposure, PPM1L dissociated with ASK1, while PP5 associated with ASK1 [4]. ASK1 also emerged in holozoa. TAK1 and ASK1 are both STE11/MAP3K kinases.
• Ceramide transport protein CERT (official symbol COL4A3BP) [1]. Human PPM1L dephosphorylates CERT in a manner depending on vesicle-associated membrane protein-associated protein A (VAPA), which is an ER resident integral membrane protein involved in recruiting lipid-binding proteins such as CERT to ER membrane. The dephosphorylation resulted in the redistribution of CERT from cytoplasm to Golgi apparatus. PPM1L also interacts with VAPA in vivo. Given that PPM1L is localized in ER, CERT is probably its physiological substrate. A model of PPM1L, VAPA, CERT and the fourth protein ACBD3 is proposed in [5]. In comparison with PPM1L, CERT and VAPA emerged much earlier: CERT is found in almost all holozoa and VAPA in almost all eukaryotes.
• IRE1 in the Endoplasmic reticulum [6]

PPM1L is down-regulated in APC mutation-negative familial colorectal cancer patients [7].

References

1. Saito S, Matsui H, Kawano M, Kumagai K, Tomishige N, Hanada K, Echigo S, Tamura S, and Kobayashi T. Protein phosphatase 2Cepsilon is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes. J Biol Chem. 2008 Mar 7;283(10):6584-93. DOI:10.1074/jbc.M707691200 |
2. Jin F, Ji C, Liu L, Dai J, Gu S, Sun X, Xie Y, and Mao Y. Molecular cloning and characterization of a novel human protein phosphatase 2C cDNA (PP2C epsilon*). Mol Biol Rep. 2004 Sep;31(3):197-202. DOI:10.1023/b:mole.0000043624.96006.eb |
3. Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, and Tamura S. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003 Apr 4;278(14):12013-21. DOI:10.1074/jbc.M211474200 |
4. Saito J, Toriumi S, Awano K, Ichijo H, Sasaki K, Kobayashi T, and Tamura S. Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase 2Cepsilon. Biochem J. 2007 Aug 1;405(3):591-6. DOI:10.1042/BJ20070231 |
5. Shinoda Y, Fujita K, Saito S, Matsui H, Kanto Y, Nagaura Y, Fukunaga K, Tamura S, and Kobayashi T. Acyl-CoA binding domain containing 3 (ACBD3) recruits the protein phosphatase PPM1L to ER-Golgi membrane contact sites. FEBS Lett. 2012 Sep 21;586(19):3024-9. DOI:10.1016/j.febslet.2012.06.050 |
6. Lu G, Ota A, Ren S, Franklin S, Rau CD, Ping P, Lane TF, Zhou ZH, Reue K, Lusis AJ, Vondriska T, and Wang Y. PPM1l encodes an inositol requiring-protein 1 (IRE1) specific phosphatase that regulates the functional outcome of the ER stress response. Mol Metab. 2013;2(4):405-16. DOI:10.1016/j.molmet.2013.07.005 |
7. Thean LF, Loi C, Ho KS, Koh PK, Eu KW, and Cheah PY. Genome-wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation-negative familial colorectal cancer patients. Genes Chromosomes Cancer. 2010 Feb;49(2):99-106. DOI:10.1002/gcc.20724 |