Phosphatase Family DSP

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP

This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.

Subfamilies

Human subfamilies

Several related subfamilies of DSP that dephosphorylate MAPK Kinases and share an N-terminal non-catalytic rhodanese domain. These are named MKP, (MAP Kinase Phosphatase). They are regulators of MAPK activity, and can mediate crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews [1, 2]). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding [1].

DSP1: inducible nuclear MKP found throughout eukaryotes

The DSP1 subfamily is an inducible nuclear MKP subfamily found throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer. Human has four members, DUSP1 (MKP1), DUSP2, DUSP4 (MKP2) and DUSP5.

DSP6: cytoplasmic MKP found throughout metazoa

The DSP6 subfamily is a cytoplasmic MKP subfamily selectively dephoshorylating ERK. It is found throughout metazoa and duplicated in vertebrates. Human genome has three members: DUSP6 (MKP3/PYST1), DUSP7 (MKPX/PYST2) and DUSP9 (MKP4/PYST3).

DSP8

The DSP8 subfamily is a metazoan subfamily that functions as an MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 (MKP7) have different tissue expression patterns.

DSP10: MKP emerged in holozoa, but lost in nematodes and rhodanese domain lost in Diptera

Human DUSP10 (MKP5) selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes. Human DUSP10 is frequently dysregulated in colorectal cancer.

STYXL1: catalytically inactive MKP conserved in metazoa but lost in ecdysozoa

The STYXL1 subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. It is also known as MK-STYX, named after the catalytically inactive phosphatase subfamily STYX. In comparison with STYX, it has an N-terminal rhodanese domain, which is a common feature between MKPs. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

Some subfamilies of DSP family lack the rhodanese domain but function in similarly to MKPs.

DSP3: eumetazoa phosphatase enriched in skeletal muscle and heart

Human DSP3s are abundantly expressed in skeletal muscle and heart. It emerged in eumetazoan, lost in nematodes and duplicated in deuterostomia and vertebrates. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.

DSP14

The DSP14 subfamily emerged in eumetazoan and duplicated in vertebrates. Human has four members, DUSP14 (MKP6), DUSP18, DUSP21 and DUSP28 (VHP). Little is known about their functions.

DSP15

The DSP15 subfamily emerged in metazoa and duplicated in vertebrates. It is characterized by a N-terminal myristoylation site which targets it to plasma membrane. Limited is known about its molecular function.

DSP19

The DSP19 subfamily is widely found in eukaryotes but absent from fungi. Human DUSP19 (SKRP1) functions in the regulation of JNK signaling but the precise molecular mechanism is unclear.

STYX: catalytically inactive phosphatase found throughout opisthokonts but lost in nematodes

The STYX subfamily is a catalytically inactive phosphatase found in most opisthokonts but lost in nematodes.

DSP23

Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

Some subfamilies of DSP family dephosphorylate non-protein substrates:

DSP12

The DSP12 subfamily is found throughout unikonts, but its function is poorly understood.

RNGTT: guanylyltransferase conserved in holozoa

The RNGTT subfamily is an mRNA capping enzyme found in holozoa. It has a phosphatase domain and guanylyltransferase.

DSP11

The DSP11 subfamily is a metazoan-specific subfamily. Its physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. Human has a single copy DUSP11 (PIR1).

Laforin

The laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. Mutations in the human member, EPM2A, are associated with myoclonic epilepsy of Lafora.

PTPMT1

The PTPMT1 subfamily is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during biosynthesis of cardiolipin. It is found in most or all animals and higher plants, and most protists but is absent from fungi, Monosiga, and some lower plants.

The subfamilies below are known or inferred to be cyclin-dependent kinase phosphatases:

CDC14

The CDC14 subfamily is a cell cycle genes widely found in eukaryotes with the exception of higher plants.

CDKN3

The CDKN3 (KAP) subfamily is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

PTPDC1

The PTPDC1 subfamily is found in holozoa and some protists, but lost from most insects. It may function in centriole and cilium biology.

Lastly, PRL and Slingshot phosphatases:

PRL

The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants (unpublished data from gOrtholog). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

Slingshot: cofilin phosphatase arose in holozoa but lost in nematodes

The slingshot subfamily is conserved in holozoan but lost in nematodes, regulates cofilin phosphorylation in opposition to LIMK and TESK kinases.

Non-human subfamilies and unclassified DSPs

Dictystelium dupA: a regulator of MAPK response to bacteria with an active kinase domain and an inactive phosphatase domain

Dictystelium DupA has an active kinase domain and an inactive phosphatase domain. The cysteine at CX₅R motif of phosphatase domain is substituted by serine, so its phosphatase domain is probably catalytically inactive. The kinase domain is pretty divergent but has the key catalytic residues. It is also found in other Dictyosteliida, but not other amoebazoa, by BLASTing against NR - eukaryotes data set and amoebazoa data set. It may regulate a MAP kinase response to bacteria Legionella pneumophila [3].

Dictystelium LRR-DSP

The LRR-DSP subfamily has LRR repeats at N-terminal. It is found in most amoebozoa by BLASTing against NR database through NCBI BLAST server.

Phosphatase domain structures

Almost all DSP phosphatase domains (PDs) have a secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTPN1. See here). The exceptions are listed below.

• The members of DSP3 and laforin families, as well as vaccinia virus DSP (PDB code: 2P4D) have an additional N-terminal helix different in structure and evolutionary origins.
• CDC14 has two tandem DSP PDs. The first PD is inactive and lacks H2, H3, E11.
• DUSP6
• RNGTT
• DUSP11
• DUSP12
• CDKN3

Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.

Accessory domains

• Most MKPs have an N-terminal domain of rhodanese fold.
• Laforin has an N-terminal carbohydrate binding domain.
• RNGTT has a C-terminal guanylyltransferase (GTase) domain.

References

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