Phosphatase Family PPM

Phosphatase Classification: PPM (PP2C)

PPM (also known as PP2C) can be 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. In contrast with PPP, which is regulated by other subunits, PPM are monomeric enzymes.

Human PPMs exclusively dephoshorylate pSer/pThr rather than pTyr. All PPMs are active, except that TAB1 has been reported as pseudophosphatase (Conner et al. 2006).

Human subfamilies

PPM1A

Named after one of the three human copies, PPM1A, PPM1B and PPM1N. It has super diverse functions. In particular, its role in MAPK signaling has been well studied in yeast, fly and human.

PPM1G

Myristoylated PPM with characteristic acidic domain inserted in catalytic domain. The subfamily is found in animals from sponge to human. It is involved in pre-mRNA splicing, histone regulation, and cell cycle.

PPM1G2

It is named as PPM1G2 because 1) its sequence is more similar to PPM1G than other PPMs, and 2) it also has myristoylated signal. It is involved in HOG pathway, inactivation of DNA damage checkpoint, and cell cycle (distinct role of PPM1G in cell cycle). It is conserved in opisthokont but lost in human and sponge.

PPM1D

PPM1D, also known as WIP1. It 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

PPM1E/F named after two human PPMs, PPM1E and PPM1F, which are also known as POXP1 and POXP2. 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

Named after one of the three copies in human, PPM1H, PPM1J and PPM1M. Little is known about them, but they are conserved in animals from sponge to human. Usually, it is single-copy in non-vertebrate from sponge to ciona as well as in fishes. Three copies are found in mammals and birds.

PPM1K

Mitochondrial phosphatase. It regulates mitochondrial permeability transition pore (MPTP), and is essential for cellular survival and development. It has been shown as branched-chain alpha-ketoacid dehydrogenase (BCKDC) phophatase (BDP), a component of BCKDC. (PS: The phylogenetic profile is strange. It is present in Monosiga, Nematostella, sea urchin and human.)

PPM1L

PPM1L locates at ER and dephoshorylate ceramide transport protein (CERT) (Ceramides is a family of lipids. They are not only structure components of lipid bilayer, but also may be involved in signaling and/or apoptosis). It also dephosphorylates two kinases TAK1 and ASK1. While PPM1L is found from fruit fly to human, the two kinases emerged as early as in holozoan.

PTC7

PTC7 is conserved through eukaryotes, but its substrate is unclear. Based upon the evidences from different species, it may be involved in various cellular processes.

PDP

This gene is the catalytic subunit of PDP (Pyruvate Dehyrogenase Phosphatase), which activates pyruvate dehyrogenase complex by dephosphorylating serine residues of E1 component. Pyruvate dehydrogenase kinases (PDKs) carry out the opposite function. Both of PDPs and PDKs are conserved from yeast to human, but PDKs rather than PDPs were lost in sponge. Human PDPs can also dephosphorylate Smads.

ILKAP

ILKAP regulates the phosphorylation state of Serine 9 of GSK3beta, with integrin-linked kinase (ILK). Both of the kinase and phosphatase are present in holozoan, but ILKAP is also found in plants.

PHLPP

PHLPP regulates and dephosphorylates kinases Akt and PKC. While its catalytic activity towards the two kinases are well known. they didn't emerged at the same time. Akt is present throughout eukaryotes and PKC is conserved in holozoan, but PHLPP is only found in bilateria.

TAB1

TAB1 is one of the multiple regulators of TGF-beta activated kinase 1 (TAK1, also called MAP3K7). They are together involved in various cellular signaling pathways. While its N-terminus interacts with TGF beta, the C-terminus of TAB1 binds to TAK1. The protein also interacts with mitogen-activated protein kinase 14 (MAPK14/p38alpha), and XIAP, a member of the inhibitor of apoptosis protein family. TAB1 is conserved from sponge to human, but the related kinases TAK1 and MAPK14 is present as deep as Monosiga and fungi, respectively.

PP2D1

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).

Other species

Fungal PTC6

Ptc6p is fungal specific and absent from Encephalitozoon of Microsporida. It locates both in the intermembrane and mitochondria. The same as PTC5, it regulates the phosphorylation state of Pda1, the E1alpha subunit of the pyruvate dehydrogenase (PDH). Though PTC5 and PTC6 share a large overlap of phenotypes, but they may have distinct functions (see Arino's review).

Fungal CYR1

CYR1 is better known as adenylate cyclase in yeast. It 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. It is not only found in Ascomycota, but also Basidiomycota (updating Newton's review).

Dictyostelium LRR-PP2C

Leucine repeats are found in various phosphatase family. It is not sure whether this is a common feature of Dictyostelium proteins or it tends to attach to phosphatases.