PPM1A explained

Protein phosphatase 1A is an enzyme that in humans is encoded by the PPM1A gene.^{[1] [2]}

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding two distinct isoforms have been described.

Interactions

PPM1A has been shown to interact with Metabotropic glutamate receptor 3.^[3] In 2006, Dr. Feng found that PPM1A can terminate TGF-beta signaling by inactivating Smad3 via dephosphorylation. Smad3 is an essential component of the TGF-beta signalling pathway.

Further reading

• Redpath NT, Price NT, Severinov KV, Proud CG . Regulation of elongation factor-2 by multisite phosphorylation . European Journal of Biochemistry . 213 . 2 . 689–99 . April 1993 . 8386634 . 10.1111/j.1432-1033.1993.tb17809.x .
• Das AK, Helps NR, Cohen PT, Barford D . Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 A resolution . The EMBO Journal . 15 . 24 . 6798–809 . December 1996 . 9003755 . 452505 . 10.1002/j.1460-2075.1996.tb01071.x.
• Takekawa M, Maeda T, Saito H . Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways . The EMBO Journal . 17 . 16 . 4744–52 . August 1998 . 9707433 . 1170803 . 10.1093/emboj/17.16.4744 .
• Fjeld CC, Denu JM . Kinetic analysis of human serine/threonine protein phosphatase 2Calpha . The Journal of Biological Chemistry . 274 . 29 . 20336–43 . July 1999 . 10400656 . 10.1074/jbc.274.29.20336 . free .
• Hishiya A, Ohnishi M, Tamura S, Nakamura F . Protein phosphatase 2C inactivates F-actin binding of human platelet moesin . The Journal of Biological Chemistry . 274 . 38 . 26705–12 . September 1999 . 10480873 . 10.1074/jbc.274.38.26705 . free .
• Cheng A, Ross KE, Kaldis P, Solomon MJ . Dephosphorylation of cyclin-dependent kinases by type 2C protein phosphatases . Genes & Development . 13 . 22 . 2946–57 . November 1999 . 10580002 . 317162 . 10.1101/gad.13.22.2946 .
• Strovel ET, Wu D, Sussman DJ . Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription . The Journal of Biological Chemistry . 275 . 4 . 2399–403 . January 2000 . 10644691 . 10.1074/jbc.275.4.2399 . free .
• Lifschitz-Mercer B, Sheinin Y, Ben-Meir D, Bramante-Schreiber L, Leider-Trejo L, Karby S, Smorodinsky NI, Lavi S . Protein phosphatase 2Calpha expression in normal human tissues: an immunohistochemical study . Histochemistry and Cell Biology . 116 . 1 . 31–9 . July 2001 . 11479720 . 10.1007/s004180100291 . 1692505 .
• Srivastava J, Goris J, Dilworth SM, Parker PJ . Dephosphorylation of PKCdelta by protein phosphatase 2Ac and its inhibition by nucleotides . FEBS Letters . 516 . 1–3 . 265–9 . April 2002 . 11959144 . 10.1016/S0014-5793(02)02500-0 .
• Ofek P, Ben-Meir D, Kariv-Inbal Z, Oren M, Lavi S . Cell cycle regulation and p53 activation by protein phosphatase 2C alpha . The Journal of Biological Chemistry . 278 . 16 . 14299–305 . April 2003 . 12514180 . 10.1074/jbc.M211699200 . free .
• Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S . Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways . Oncogene . 22 . 21 . 3307–18 . May 2003 . 12761501 . 10.1038/sj.onc.1206406 . 38880905 .
• Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P . Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 26 . 16006–11 . December 2003 . 14663150 . 307683 . 10.1073/pnas.2136600100 . 2003PNAS..10016006F . free .
• Yoshizaki T, Maegawa H, Egawa K, Ugi S, Nishio Y, Imamura T, Kobayashi T, Tamura S, Olefsky JM, Kashiwagi A . Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes . The Journal of Biological Chemistry . 279 . 21 . 22715–26 . May 2004 . 15016818 . 10.1074/jbc.M313745200 . free .
• Li D, Wang F, Lai M, Chen Y, Zhang JF . A protein phosphatase 2calpha-Ca2+ channel complex for dephosphorylation of neuronal Ca2+ channels phosphorylated by protein kinase C . The Journal of Neuroscience . 25 . 8 . 1914–23 . February 2005 . 15728831 . 10.1523/JNEUROSCI.4790-04.2005 . 6726054 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, Kawashima SA, Watanabe Y . Shugoshin collaborates with protein phosphatase 2A to protect cohesin . Nature . 441 . 7089 . 46–52 . May 2006 . 16541025 . 10.1038/nature04663 . 2006Natur.441...46K . 4425074 .

Notes and References

1. Mann DJ, Campbell DG, McGowan CH, Cohen PT . Mammalian protein serine/threonine phosphatase 2C: cDNA cloning and comparative analysis of amino acid sequences . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1130 . 1 . 100–4 . February 1992 . 1311954 . 10.1016/0167-4781(92)90471-b .
2. Web site: Entrez Gene: PPM1A protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform.
3. Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P . Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 26 . 16006–11 . December 2003 . 14663150 . 307683 . 10.1073/pnas.2136600100 . 2003PNAS..10016006F . free .