Difference between revisions of "Phosphatase Family PPM"

Revision as of 21:37, 16 June 2015

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

PPM (a.k.a. PP2C) is serine/threonine phosphatase found in all the eukaryotes. Even in bacteria and archaea, there is a family called SpoIIE, governs the phoshorylation state of a protein regulating transcription factor sigma F during sporulation in Bacillus subtilis. Human PPMs exclusively dephoshorylate pSer/pThr. All PPMs are active, except that TAB1 has been reported as pseudophosphatase (Conner et al. 2006). In contrast with the serine/threonine phosphatases of PPP family which carries out activity through protein complexes consisting of catalytic subunits and regulatory subunits, most PPM are monomeric enzymes.

Many if not most PPMs requires two even three metal ion, either Mg²⁺ or Mn²⁺ to activate its phosphatase activity [1].

Subfamilies

PPM1A

The subfamily is named after one of the three human copies, PPM1A (PP2Cα), PPM1B (PP2Cβ) and PPM1N. It is involved in different pathways, such as MAPK, SAPK/JNK, TGF-beta, NF-kappaB signaling. PPM1As were found across holozoa.

PPM1G (PP2Cγ): mRNA splicing and histone regulation

The PPM1G subfamily is found across metezoa. PPM1G has a predicted N-terminal myristoylation site, C-terminal nuclear localization signaling, and a characteristic phosphatase domain inserted by an acidic domain. It is involved in pre-mRNA splicing, histone regulation, and cell cycle.

PPM1D (WIP1): oncogene in different cancer types

The PPM1D subfamily is an oncogene conserved from Monosiga to human. It regulates cell homeostasis in response to DNA damage. It dephosphorylates p53 and its various target kinases, such as ATM, Chk1 and Chk2. It also dephosphorylates p38/MAPK, tumor suppressors INK4A and ARF, RelA subunit of NF-kappaB, gamma-H2AX and etc. (PS: ATM and PPM1D have a significant overlap of their substrate proteins, -the same residues on a set of proteins, including p53, Mdm2, Chk2 and gamma-H2AX at least.)

PPM1E (POXP): the phosphatases of CAMKs and PAK

The PPM1E subfamily is named after two human PPMs, PPM1E (also known as POXP1, PP2CH, caMKN, CaMKP-N) and PPM1F (also known as POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g and PAK, and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

PPM1H

The PPM1H subfamily is named after one of the three copies in human, PPM1H (URCC2, ARHCL1, NERPP-2C), PPM1J (PP2Cζ) and PPM1M (PP2Cη), which are expressed in distinct tissues. The PPM1H subfamily are conserved in animals from sponge to human. Usually, it is single-copy in invertebrates from sponge to ciona. The three copies are found in mammals probably arose by two independent duplication events (not whole-genome duplication).

PPM1K (PP2Cκ, PP2Cm, BDP): mitochondrial phosphatase lost in ecdysozoa

The PPM1K subfamily is a mitochondrial phosphatase that regulates mitochondrial permeability transition pore (MPTP). It also dephosphorylates branched-chain alpha-ketoacid dehydrogenase complex. The PPM1K subfamily emerged in holozoan and lost in ecdysozoa.

PPM1L (PP2Cε, PP2Ce)

Human PPM1L is a phosphatase resident in ER, where it dephoshorylates ceramide transport protein (CERT). It also dephosphorylates two kinases TAK1 and ASK1. While PPM1L emerged in bilateria, all its known substrates emerged in holozoa or earlier.

PTC7: activating Q6 biosynthesis

The PTC7 subfamily is conserved through eukaryotes, dephosphorylates the mitochondrial hydroxylase COQ7 and activates Q6 biosynthesis.

PDPc: the catalytic subunit of pyruvate dehyrogenase phosphatase

The PDPc subfamily is the catalytic subunit of Pyruvate Dehyrogenase Phosphatase (PDP). It is found throughout eukaryotes, so are Pyruvate Dehyrogenase Kinase (PDK) and its substrate Pyruvate Dehyrogenase Complex (PDC). Different from other PPMs, it functions in a manner of heterodimer rather than monomer.

ILKAP (PP2Cδ): a subunit of TAK1-TAB1 complex

The name of ILKAP subfamily stands for integrin-linked kinase (ILK) associated phosphatase. It directly binds to ILK and specifically regulates one of the two substrates of ILK, Ser-9 on glycogen synthase kinase 3 β (GSK3β). It also dephosphorylates p90 ribosomal S6 kinase 2 (RSK2) at multiple serine or threonine sites in the nuclear. All the three, ILKAP, ILK and RSK2, emerged in holozoa, but ILKAP was lost in arthropods, while ILK and RSK2 were not.

PHLPP: AGC kinase phosphatase

The subfamily is characterized by PH domain and Leucine rich repeats. It dephosphorylates AKT/PKB, PKC and S6 kinase families of AGC kinase group at serines in hydrophobic motif site. The subfamily is found across bilateria.

TAB1: binding to TAK1 and p38 and inducing their autophosphorylation

The TAB1 subfamily is most well known for its binding to MAPKs TAK1 and p38. It does not dephosphorylate them. Instead, it binds to them and induces their autophosphorylation. It is found in metazoa except Drosophila. It is found in most other arthropods, which indicates a lineage-specific gene loss in Drosophila. Interestingly, TAK1 and p38 are found in Drosophila and both of them emerged earlier, in holozoa and opisthokont, respectively.

PP2D1

The function of the PP2D1 subfamily is unknown. It is found in frog, birds, platypus and mammals. It is also found sparsely from Trichoplax to fish, including Nematostella, Saccoglossus, Ciona, lancelets, and Tetraodon (but not zebrafish). It has a predicted nuclear localization signaling (NLS) at the N-terminal.

CG9801

The CG9801 subfamily found in metazoa but lost in deuterostome. Its function is unclear. Dictyostelium also has CG9801 and expanded into four members, including one involved in early tip formation.

PPM1Z: a phosphatase lost in jawed vertebrates

The function of this subfamily is unclear. It emerged in holozoa or metazoa through the duplication of its common ancestral gene with PPM1A.

LRR-PPM

The LRR-PP2C subfamily has a unique domain combination of leucine riches repeats (LRRs) and PPM phosphatase domain. It is mainly found in Dictyostelid.

KAPP-like

The subfamily is mainly found in close to plant PPM phosphatase KAPP (see [1]), a regulator of the receptor-like kinase (RLK) signaling pathway. Plant RLKs are counterpart of animal receptor kinases. But, the subfamily is mainly found in Dictyostelid . It may not function in the same way as plant KAPPs, since it does not the FHA domain common in plant KAPPs.

Unclassified phosphatases

Below are unclassified phosphatases of PPM family, the functions of which have been known.

• Budding yeast PTC1. Its functions have been reviewed in [2, 3]. PTC1 is found in most fungi (see our internal data).

• Budding yeast PTC6 is found in a broad of fungi except Encephalitozoon of Microsporida. In budding yeast, Ptp6p locates both in the intermembrane and mitochondria. The same as Ptc5p, it regulates the phosphorylation state of Pda1p, the E1alpha subunit of the pyruvate dehydrogenase (PDH). Though PTC6 and PTC5 (of PDPc subfamily share a large overlap of phenotypes, but they may have distinct molecular functions [2].

• Budding yeast CYR1 encodes adenylate cyclase in budding yeast. The protein has a domain combination of 1) Adenylate cyclase G-alpha binding domain, 2) Ubiquitin domain CYR1 adenylate cyclase, 3) Leucine repeats, 4) PPM phosphatase domain, and 5) cyclase homology domain. CYR1 is found in most fungi both Ascomycota and Basidiomycota (also see Newton's review). CYR1 is close to PHLPP in phosphatase domain sequence, but they have distinct domain structure and molecular function.

• Dictyostelium spnA has two domains, Galpha subunit family of GTP binding proteins at N-terminal, and PPM phosphatase domain at C-terminal. It functions in cell autonomous for prestalk differentiation, and cell non-autonomous for pre spore differentiation (see summary from DictyBase).

References

1. Tanoue K, Miller Jenkins LM, Durell SR, Debnath S, Sakai H, Tagad HD, Ishida K, Appella E, and Mazur SJ. Binding of a third metal ion by the human phosphatases PP2Cα and Wip1 is required for phosphatase activity. Biochemistry. 2013 Aug 27;52(34):5830-43. DOI:10.1021/bi4005649 | PubMed ID:23906386 | HubMed [Tanoue13]
2. Ariño J, Casamayor A, and González A. Type 2C protein phosphatases in fungi. Eukaryot Cell. 2011 Jan;10(1):21-33. DOI:10.1128/EC.00249-10 | PubMed ID:21076010 | HubMed [Arino11]
3. Sharmin D, Sasano Y, Sugiyama M, and Harashima S. Effects of deletion of different PP2C protein phosphatase genes on stress responses in Saccharomyces cerevisiae. Yeast. 2014 Oct;31(10):393-409. DOI:10.1002/yea.3032 | PubMed ID:25088474 | HubMed [Sharmin14]