Phosphatase Family PPM

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, PPM are monomeric enzymes.

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)

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)

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 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. Little is known about their physiological substrates. 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): 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

Human 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

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

PDP: catalytic subunit of pyruvate dehyrogenase phosphatase

The PDP subfamily 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: GSK3β phosphatase

Human 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: AGC kinase phosphatase found in bilateria

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 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 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).

• CG9801 is found in metazoa but lost in deuterostome. Dictyostelium also has CG9801 and expanded into four members. Its function is unclear.

• PPM1G2 is named as PPM1G2 because it has a N-terminal myristoylation signal and it is closer to PPM1G than other PPMs in sequence, though it lacks the acidic domain inserted in phosphatase domain. It is involved in HOG pathway, inactivation of DNA damage checkpoint, and cell cycle. It is conserved in opisthokont but lost in human, sponge and monosiga. The best characterized phosphatases of this subfamily are yeast Ptc2, Ptc3 and Ptc4.

• Dictyostelium LRR-PP2C is characterized by leucine repeats 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.

• Dictyostelium KAPP-like is a subfamily close to plant phosphatase KAPP (see [1]). Plant KAPPs have a FHA domain, but Dicty KAPP-like gene do not.

Unclassified phosphatases

• Fungal PTC1.

• Fungal PTC6 is fungal specific subfamily 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 PTC5 and PTC6 share a large overlap of phenotypes, but they may have distinct functions (see Arino's review).

• Fungal 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 a fungal specific subfamily 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.