Difference between revisions of "Phosphatase Family DSP"

Revision as of 00:46, 13 May 2015

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

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. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews [1, 2]). It worthy pointing out that the Rhodanese domains at N-terminus usually contain kinase-interacting motifs (KIMs) for MAPK binding [1].

• DSP1 subfamily is inducible nuclear MKP subfamily conserved 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 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 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 (MKP7) have different tissue expression patterns.

• DSP10 (MKP5) subfamily selectively dephosphorylates p38 and JNK. It is conserved across holozoan but lost in nematodes. Human DUSP10 is frequently unregulated in colorectal cancer.

• STYXL1 (MK-STYX) subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. 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 subfamily is a subfamily 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 subfamily is a 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 subfamily subfamily emerged in metazoa and duplicated in vertebrates. It is characterized by a N-termnal myristoylation site which targets it to plasma membrane. Limited is known about its molecular function.

• 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 metazoa but lost in ecdysozoa.

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 or inferred to be cyclin-dependent kinase phosphatases:

• 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 Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

• PTPDC1 subfamily 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 (unpublished data from gOrtholog).

• Slingshot subfamily, a subfamily conserved in holozoan but lost in nematodes, regulates cofilin phosphorylation in opposition to LIMK and TESK kinases.

References

1. Dickinson RJ and Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases. J Cell Sci. 2006 Nov 15;119(Pt 22):4607-15. DOI:10.1242/jcs.03266 | PubMed ID:17093265 | HubMed [Dickinson06]
2. Caunt CJ and Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 2013 Jan;280(2):489-504. DOI:10.1111/j.1742-4658.2012.08716.x | PubMed ID:22812510 | HubMed [Caunt13]