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.

Several related subfamilies of DSP that dephosphorylate MAPK Kinases and share an N-terminal non-catalytic rhodanese domain. These subfamilies are so-called MKP, short for MAP Kinase Phosphatase. The Rhodanese domains are regulatory and targeting, and include kinase-interacting motifs (KIMs) for MAPK binding [1].

• DSP1 subfamily is also known as inducible nuclear MKPs, which has four members in human, DUSP1 (MKP-1), DUSP2 (PAC-1), DUSP4 (MKP-2) and DUSP5 (hVH3). The subfamily is found in animals, plants, amoeba, and a few basal eukaryotes, but is absent from ecdysozoa (nematode and arthropoda), most fungi and monosiga (unpublished data, DUSP1, DUSP2, DUSP4, DUSP5).

• DSP6 subfamily consists of cytoplasmic ERK-specific MKPs, with three human members, DUSP6 (MKP-3), DUSP7 (MKP-X) and DUSP9 (MKP-4). The subfamily is found throughout metazoa.

• DSP8 subfamily is a metazoan subfamily that functions as 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 have different tissue expression patterns.

• DSP10 (MKP5) subfamily selectively dephosphorylates p38 and JNK. It is conserved across holozoan but lost in nematodes.

• STYXL1 (MK-STYX) subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoan but lost in ecdysozoan. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

Some subfamilies of DSP family lack rhodanese domain but functions in similar manners with MKPs.

• DSP3 subfamily

• DSP14 subfamily has four members in human, DUSP14, DUSP18, DUSP21, DUSP28. It is found in eumetazoa.

• DSP15 subfamily

• DSP19 (SKRP1) subfamily is a phosphatase subfamily widely found in eukaryotes but absent from fungi. It functions in the regulation of JNK signaling but the precise molecular mechanism is unclear.

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

• DSP23 (VHZ) subfamily is a nuclear phosphatase found in metazoan but lost in ecdysozoan.

Some subfamilies of DSP family dephosphorylate non-protein substrates:

• DSP12 subfamily is a subfamily conserved throughout unikonts, but its function is poorly understood.

• RNGTT subfamily is mRNA capping enzyme found in holozoan. It has a phosphatase domain and guanylyltransferase.

• DSP11 (PIR1) subfamily is a metazoan-specific subfamily. Its exact physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing.

• Laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. It has a single human member, EPM2A, mutations of which have been associated with myoclonic epilepsy of Lafora.

• PTPMT1 subfamily is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during de novo 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 as or supposed to be cyclin-dependent kinase phosphatase:

• CDC14 subfamily consists of cell cycle genes widely found in eukaryotes with the exception of higher plants.

• CDKN3 (KAP) subfamily is a chordate-specific subfamily targeting threonine Cyclin-dependent kinases (CDKs) CDK1/CDC2 and CDK2. It is usually one copy per chordate genome.

• PTPDC1 subfamily (aka PTP9Q22) is found in holozoa and some protists, but lost from most insects. It may function in centriole and cilium biology.

Last, PRL and Slingshot phosphatases:

• PRL subfamily is short for Phosphatases of Regenerating Liver. There are three PRLs in human, PRL1, PRL2, PRL3, all of which have been identified as key contributors to metastasis in several human cancers. PRL subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants (unpublish data from gOrtholog).

• Slingshot subfamily, a subfamily conserved in holozoan but lost in nematodes, regulates cofilin phosphorylation with LIMKs and TESK kinases.