Phosphatase Subfamily PPM1A

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1A

Evolution

The PPM1A subfamily is found across holozoan.

PPM1A and PPM1B probably arose by gene duplication in vertebrates, but not through whole-genome duplication, since they do not locate in double-conserved synteny.

PPM1N probably emerged in placentals and lost by independent evolutionary events in different lineages, as implied by internal orthology database and BLAST NR database. For BLAST, human PPM1N was defined as the hits that have a better (lower) E-values than human PPM1A and PPM1B.

Functions

Human PPM1A

Human PPM1A or PPM1B results in dephosphorylation of IKKβ at Ser-177 and Ser-181 and termination of IKKβ-induced NF-κB activation [1].

Human PPM1B

PPM1B is expressed in a broad types of tissues, most abundantly in skeletal muscle as shown by RNA-seq data from GTEx and northern blot [2]. The substrates of PPM1B include:

• TAK1.
• TBK1 at Ser-172. TBK1 is a kinase activates antiviral response. The dephosphorylation therefore results in negatively regulates antiviral response [3].

PPM1B is phosphorylated by PKA at Ser-195 [4]. The Ser-195 is a signature of PPM1A subfamily, because 1) all PPM1A members have serine at the position, 2) PPMs of other subfamilies only have serine, occasionally.

PPM1B is modified with ISG15 at least through Lys-12 and Lys-142 [5]. ISG15 is an interferon-upregulated ubiquitin-like protein, which is covalently conjugated to various cellular proteins (ISGylation). ISG15 is found mainly in marsupials and placentals. In comparison, Lys-12 is found in all vertebrate PPM1Bs and PPM1As. Lys-142 is only found in primate and eutheria PPM1Bs, and was replaced by Thr in rodent PPM1B, by Asp or Glu even Ser in marsupial, reptile and fish PPM1Bs, by Gln and Ser even His in PPM1A.

Human PPM1N

PPM1N's function is unknown. It is generally expressed at low level across tissues except spleen (see RNA-seq data from GTEx).

Fruit fly alph (alphabet): negatively regulates RAS/MAPK and SAPK

Alphabet, the PPM1A in fruit fly, negatively regulates RAS/MAPK signaling in Drosophila [6] and stress-activated protein kinase (SAPK) [7]. However, its substrates in these signaling pathways are unclear.

References

1. Sun W, Yu Y, Dotti G, Shen T, Tan X, Savoldo B, Pass AK, Chu M, Zhang D, Lu X, Fu S, Lin X, and Yang J. PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. Cell Signal. 2009 Jan;21(1):95-102. DOI:10.1016/j.cellsig.2008.09.012 |
3. Zhao Y, Liang L, Fan Y, Sun S, An L, Shi Z, Cheng J, Jia W, Sun W, Mori-Akiyama Y, Zhang H, Fu S, and Yang J. PPM1B negatively regulates antiviral response via dephosphorylating TBK1. Cell Signal. 2012 Nov;24(11):2197-204. DOI:10.1016/j.cellsig.2012.06.017 |
4. Choi HK, Park SY, Oh HJ, Han EJ, Lee YH, Lee J, Jun WJ, Choi KC, and Yoon HG. PKA negatively regulates PP2Cβ to activate NF-κB-mediated inflammatory signaling. Biochem Biophys Res Commun. 2013 Jul 5;436(3):473-7. DOI:10.1016/j.bbrc.2013.05.129 |
5. Takeuchi T, Kobayashi T, Tamura S, and Yokosawa H. Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation. FEBS Lett. 2006 Aug 7;580(18):4521-6. DOI:10.1016/j.febslet.2006.07.032 |
6. Baril C and Therrien M. Alphabet, a Ser/Thr phosphatase of the protein phosphatase 2C family, negatively regulates RAS/MAPK signaling in Drosophila. Dev Biol. 2006 Jun 1;294(1):232-45. DOI:10.1016/j.ydbio.2006.02.046 |
6. Baril C, Sahmi M, Ashton-Beaucage D, Stronach B, and Therrien M. The PP2C Alphabet is a negative regulator of stress-activated protein kinase signaling in Drosophila. Genetics. 2009 Feb;181(2):567-79. DOI:10.1534/genetics.108.096461 |
8. Marley AE, Kline A, Crabtree G, Sullivan JE, and Beri RK. The cloning expression and tissue distribution of human PP2Cbeta. FEBS Lett. 1998 Jul 10;431(1):121-4. DOI:10.1016/s0014-5793(98)00708-x |