Phosphatase Family DSP

Phosphatase Classification: Superfamily CC1: Family DSP

This family consists of the dual-specific protein phosphatases (DSPs). Not all so-called DSPs are protein phosphatases. For instance, PTPMT1 is phosphatidylglycerolphosphate phosphatase, Laforin is glucan phosphatase. Based upon sequence similarity, domain combination and known functions, the subfamilies of DSP can be grouped as below.

MKP is short for MAP kinase phosphatase, where MAP stands for Mitogen-Activated Protein. As implied by its name, MKP is involved in MAPK signaling cascades. A feature of MKPs are that they have an N-terminal rhodanese. Unlike the rhodanese domain in CDC25 phosphatase which carries out phosphatase activity, the rhodanese domain in MKP is inactive. Instead, it contains kinase-interacting motifs (KIMs) for MAPK binding [1].

DSP1 subfamily

The 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amoeba, and a few basal eukaryotes, but is absent from ecdysozoa (nematode and arthropoda), most fungi and monosiga (unpublished data, DUSP1, DUSP2, DUSP4, DUSP5).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

The subfamily is also known as cytoplasmic ERK-specific MKPs, which includes three members in human, DUSP6 (MKP- 3), DUSP7 (MKP-X) and DUSP9 (MKP-4). The subfamily is found throughout metazoan.

DSP8 subfamily

The subfamily has two members in human, DUSP8 (hVH5) and DUSP16 (MKP-7). Different from DSP1 and DSP6 subfamilies, it is supposed to be JNK/p38 selective. It is found in metazoan except arthropoda.

DSP10 subfamily

The only member in human is DSP10 (MKP5). Similar to DSP8 subfamily, it is supposed to be JNK/p38 selective. It is found in most metazoan except nematodes.

STYXL1 subfamily

STYXL1 subfamily is pseudophosphatase (catalytically inactive). It has a single member in human, STYXL1 (MK-STYX). It is found in metazoan but lost in ecdysozoa (arthropoda and nematoda).

Atypical DSPs that may act as MKPs

Here, Atypical generally means these DSPs lack rhodanese domain found in MKPs. Some of these Atypical DSPs are MAPK phosphatases, although they do not have rhodanese domain (perhaps, they harbor kinase-interacting motif somewhere else instead of within rhodanese domain). In general, Atypical DSPs have various physiological substrates.

DSP3 subfamily

The subfamily DSP3 consists of five genes in human, DUSP3, DUSP13, DUSP26 (chr 8, also called MKP8, DUSP24), DUSP27 (chr 1), DUPD1 (chr 10, it has an alias of DUSP27). It is found in eumetazoan but lost in nematodes.

DSP14 subfamily

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

DSP15 subfamily

DSP15 subfamily has two members in human, DUSP15 and DUSP22. The subfamily is characterized by a N-terminal myristoylation site. It is found throughout metazoan (see gOrtholog).

DSP19 subfamily

DSP19 subfamily has a single member in human DUSP19 (SKRP1). It is found in most eukaryotes except fungi (unpublished data from gOrtholog). DUSP19 appears to play a specific role in the regulation of jun-kinase (JNK) signaling; however, the precise mechanism by which it regulates this pathway remains controversial.

STYX subfamily

STYX subfamily is pseudophosphatase. It has a single member in human STYX. STYX localizes to the nucleus, competes with DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export [2]. The subfamily is found in most opisthokonts but lost in nematodes. Although It is not found in Drosophila and budding yeast, it is found in other arthropoda and fungi (unpublished data from gOrtholog).

DSP23 subfamily

DSP23 subfamily has a single member in human, DUSP23. It is found in metazoan but lost in nematodes and most arthropoda (unpublished data from gOrtholog). Its physiological substrate is unclear.

Other atypical DSPs

DSP12 subfamily

The subfamily is conserved throughout unikonts and usually a single copy in each genome. The human DUSP12 is localized primarily in the nucleus and is involved in glucokinase regulation. The yeast ortholog YHV1 is a tyrosine-specific protein phosphatase associates with pre-60S ribosome.

RNGTT subfamily

RNGTT is RNA guanylyltransferase and 5'-phosphatase. Besides phosphatase domain, it has mRNA capping enzyme domain. It is ubiquitous in eukaryotes and usually there is a single copy in each organism (unpublished data from gOrtholog).

DSP11 subfamily

DSP subfamily has a single member in human, DUSP11 (PIR1). Its exact physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. This is not surprising given that it is close to another atypical DSP, RNGTT, RNA guanylyltransferase and 5'-phosphatase. DSP11 subfamily is found through metazoan (unpublished data from gOrtholog).

Laforin subfamily

Laforin subfamily has a single copy in human, EPM2A. As implied by its name, mutations in this gene have been associated with myoclonic epilepsy of Lafora. Laforin subfamily is mostly found in vertebrates. It is characterized by a carbohydrate-binding domain. It is supposed to dephosphorylate glycogen.

PTPMT1 subfamily

PTPMT1 is a mitochondrial phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, a critical step in the de novo biosynthesis of cardiolipin. It is found in most or all animals and higher plants, but is absent from fungi, Monosiga, and lower plants. It is also found in several protists, including Dictyostelium , Leishamania, Trypanosomes, Ectocarpus, and diatoms. More surprisingly, a functional PTPMT1 is found in a eubacterium Rhodopirellula baltica. Read more.

PRL

PRL subfamily

PRL 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). Read more.

CDK phosphatases

The subfamilies below are known as or supposed to be cyclin-dependent kinase phosphatase.

CDC14 subfamily

CDC14 subfamily is found throughout eukaryotes (unpublished data from gOrtholog), but may have different functions [3]. It has three copies in human, CDC14A, CDC14B and CDC14C.

CDKN3 subfamily

CDKN3 subfamily is found in vertebrates, usually one copy per organism. Human CDKN3 inhibits cyclin-dependent kinase (CDK) by interacting with and dephosphorylating CDK2 kinase.

PTPDC1 subfamily

PTPDC1 (aka PTP9Q22) is found in holozoa (monosiga + metazoa) and excavata. It is absent from most of arthropoda. It is function is unclear. Human PTPDC1 has a C-terminal region to the predicted phosphatase catalytic domain.

Slingshot

Slingshot subfamily

Slingshot subfamily consists for three genes in human, SSH1, SSH2, SSH3. Slingshot phosphatases dephosphorylates ADF and cofilin, and thus suppresses actin filament assembly induced by the kinases TESK1 (testis-specific kinase 1) and LIMK1 (LIM domain kinase 1). Slingshot subfamily is most likely to emerge in holozoan (monosiga + metazoan).