Phosphatase Subfamily PPM1H

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1H

Evolution

The PPM1H subfamily are found throughout animals from sponge to human. In invertebrates, it usually has a single copy per genome. Human has three copies, arose by two independent duplication events. The genes PPM1H and PPM1J emerged by duplication in early vertebrates or chordates; the gene PPM1M emerged later in sarcopterygii (lobe-finned fish + terrestrial vertebrates). Neither of the duplication events were whole-genome duplication, as evidenced by no obvious double-conserved synteny were detected.

Domain

The PPM1H subfamily has a single structural domain, phosphatase domain. No obvious target peptide has been found so far, so PPM1Hs probably functions mainly in cytoplasm.

Functions

Tissue-specific expression and subcellular localization

The three human members have distinct expression pattern across tissues, according the RNA-seq data from GTEx and studies on individual phosphatases by northern blot analysis or similar assays. They are expressed in a broad types of tissues, but most abundantly in different tissues:

• PPM1H in brain, localized in neurites, growth cones and nucleus of neurons [1].
• PPM1J in testis [2].
• PPM1M in white cell and spleen, localized mainly in cell nuclei [3].

In addition, PPM1H is over-expressed in colon cancer cell lines, where PPM1H is localized in cytoplasm [4].

Substrates and interacting parterns

PPM1H directly interacted with Smad1/5/8 through its Smad-binding domain, and dephosphorylates phospho-Smad1/5/8 (P-Smad1/5/8) in the cytoplasm [5]. The Smad1/2/8 are critical players in bone morphogenetic protein (BMP) signaling, which are also phosphorylated by PPM1A [6].

PPM1H was found to dephosphorylate the tumor suppressor p27 at Thr-187, in a search for trastuzumab (Herceptin) resistance mechanism(s) by RNAi screening [7]. The dephosphorylation remove a signal for proteasomal degradation from p27.

PPM1H also associatesd with and probably dephosphorylates CSE1L, a proliferation and apoptosis-related protein [4].

PPM1J associated with ubiquitin conjugating enzyme 9 (UBC9) [2].

PPM1M dephosphorylated IKKβ in vitro [8].

References

1. Labes M, Roder J, and Roach A. A novel phosphatase regulating neurite extension on CNS inhibitors. Mol Cell Neurosci. 1998 Sep;12(1-2):29-47. DOI:10.1006/mcne.1998.0692 |
2. Kashiwaba M, Katsura K, Ohnishi M, Sasaki M, Tanaka H, Nishimune Y, Kobayashi T, and Tamura S. A novel protein phosphatase 2C family member (PP2Czeta) is able to associate with ubiquitin conjugating enzyme 9. FEBS Lett. 2003 Mar 13;538(1-3):197-202. DOI:10.1016/s0014-5793(03)00153-4 |
3. Komaki K, Katsura K, Ohnishi M, Guang Li M, Sasaki M, Watanabe M, Kobayashi T, and Tamura S. Molecular cloning of PP2Ceta, a novel member of the protein phosphatase 2C family. Biochim Biophys Acta. 2003 Nov 30;1630(2-3):130-7. DOI:10.1016/j.bbaexp.2003.09.004 |
4. Sugiura T, Noguchi Y, Sakurai K, and Hattori C. Protein phosphatase 1H, overexpressed in colon adenocarcinoma, is associated with CSE1L. Cancer Biol Ther. 2008 Feb;7(2):285-92. DOI:10.4161/cbt.7.2.5302 |
5. Shen T, Sun C, Zhang Z, Xu N, Duan X, Feng XH, and Lin X. Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H. Cell Res. 2014 Jun;24(6):727-41. DOI:10.1038/cr.2014.48 |
6. Duan X, Liang YY, Feng XH, and Lin X. Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway. J Biol Chem. 2006 Dec 1;281(48):36526-32. DOI:10.1074/jbc.M605169200 |
7. Lee-Hoeflich ST, Pham TQ, Dowbenko D, Munroe X, Lee J, Li L, Zhou W, Haverty PM, Pujara K, Stinson J, Chan SM, Eastham-Anderson J, Pandita A, Seshagiri S, Hoeflich KP, Turashvili G, Gelmon KA, Aparicio SA, Davis DP, Sliwkowski MX, and Stern HM. PPM1H is a p27 phosphatase implicated in trastuzumab resistance. Cancer Discov. 2011 Sep;1(4):326-37. DOI:10.1158/2159-8290.CD-11-0062 |
8. Henmi T, Amano K, Nagaura Y, Matsumoto K, Echigo S, Tamura S, and Kobayashi T. A mechanism for the suppression of interleukin-1-induced nuclear factor kappaB activation by protein phosphatase 2Ceta-2. Biochem J. 2009 Sep 14;423(1):71-8. DOI:10.1042/BJ20090208 |