Dual-specificity phosphatase is a form of phosphatase that can act upon tyrosine or serine/threonine residues.[1]
There are several families of Dual-Specificity Phosphatase (DUSP) enzymes in mammals. All share a similar catalytic mechanism, by which a conserved cysteine residue forms a covalent intermediate with the phosphate group to be eliminated. The residues surrounding their calatytic core obey a rather strict consensus: His-Cys-x-x-x-x-x-Arg-Ser. The serine side chain and an additional conserved aspartate play a central role in the elimination of the Cys-linked intermediate, thus completing their enzymatic cycle.[2] The main difference between tyrosine-specific phosphatases and dual-specificity phosphatases lies in the width of the latter enzymes' catalytic pocket: thus they can accommodate phosphorylated serine or threonine side chains as well as phosphorylated tyrosines.[3]
Classification
The human genome encodes at least 61 different DUSP proteins. The following major groups or families of DUSPs were identified:[3]
There are three members of this family (SSH1L, SSH2L and SSH3L) with broad specificity. They contain SH3-binding motifs as well as F-actin binding motifs, thus they are generally believed to play a role in the regulation of cytoskeletal rearrangements. In accordance with their proposed rule, proteins like ADF, cofilin and LIMK1 are slingshot substrates.
- Phosphatases of Regenerating Liver (PRLs):
Three PRL genes were described in mammals (PRL-1, PRL-2 and PRL-3). They share a high sequence identity and possess an N-terminal prenylation sequence (CAAX box). Despite their up-regulation in colorectal cancer, the role and substrate specificity of PRLs is poorly known.
The four mammalian Cdc14 proteins (named KAP, Cdc14A, Cdc14B and PTP9Q22) play a crucial role in cell cycle regulation by dephosphorylating cyclin-dependent kinases, most importantly CDK2.
- PTEN and myotubularin phosphatases
There are five PTEN-like phosphatases encoded in the human genome. Though structurally related to other DUSPs, these are not strictly phosphorotein-phosphatases, since their most important substrates are phosphorylated inositol lipids. Myotubularins similarly display a preference towards certain phosphatidyl inositols.
- Mitogen-activated protein Kinase Phosphatases (MKPs)
MKPs form a rather large family, with some 11 well-characterized members. They are responsible for the dephosphorylation of active mitogen-activated protein kinases (MAPKs). In accordance with this role, several (but not all) MKPs contain an additional, N-terminal domain. Although structurally similar to Cdc14, this extra domain is inactive, and plays a role in substrate recruitment. The surface of this substrate-binding domain mimics the D-motifs found in intrinsically disordered substrates of MAPKs.
- In addition, there are several dual-specificity phosphatases lacking close relatives. Most of these atypical DUSPs are poorly characterized. Some of them are probably inactive, and only mediate protein-protein interactions.
References
- ^ Dual-Specificity Phosphatases at the US National Library of Medicine Medical Subject Headings (MeSH)
- ^ Denu JM, Dixon JE (June 1995). "A catalytic mechanism for the dual-specific phosphatases". Proc. Natl. Acad. Sci. U.S.A. 92 (13): 5910–4. doi:10.1073/pnas.92.13.5910. PMC 41611. PMID 7597052.
- ^ a b Patterson KI, Brummer T, O'Brien PM, Daly RJ (March 2009). "Dual-specificity phosphatases: critical regulators with diverse cellular targets". Biochem. J. 418 (3): 475–89. PMID 19228121.
Intracellular signaling peptides and proteins
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MAP |
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Calcium |
- Intracellular calcium-sensing proteins
- Calcineurin
- Ca2+/calmodulin-dependent protein kinase
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G protein |
Heterotrimeric |
cAMP: |
- Heterotrimeric G protein
- Adenylate cyclase
- cAMP
- 3',5'-cyclic-AMP phosphodiesterase
- Protein kinase A
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cGMP: |
- Transducin
- Gustducin
- Guanylate cyclase
- cGMP
- 3',5'-cyclic-GMP phosphodiesterase
- Protein kinase G
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- G alpha subunit Gα
- GNAO1
- GNAI1
- GNAI2
- GNAI3
- GNAT1
- GNAT2
- GNAT3
- GNAZ
- GNAS
- GNAL
- GNAQ
- GNA11
- GNA12
- GNA13
- GNA14
- GNA15/GNA16
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- G beta-gamma complex Gβ
- Gγ
- GNGT1
- GNGT2
- GNG2
- GNG3
- GNG4
- GNG5
- GNG7
- GNG8
- GNG10
- GNG11
- GNG12
- GNG13
- BSCL2
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- G protein-coupled receptor kinase
- AMP-activated protein kinase
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Monomeric |
- ARFs
- Rabs
- Ras
- Rhos
- Arfs
- Ran
- Rhebs
- Raps
- RGKs
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Cyclin |
- Cyclin-dependent kinase inhibitor protein
- Cyclin-dependent kinase
- Cyclin
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Lipid |
- Phosphoinositide phospholipase C
- Phospholipase C
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Other protein kinase |
Serine/threonine: |
- Casein kinase
- eIF-2 kinase
- Glycogen synthase kinase
- GSK1
- GSK2
- GSK-3
- GSK3A
- GSK3B
- IκB kinase
- Interleukin-1 receptor-associated kinase
- Lim kinase
- p21-activated kinases
- Rho-associated protein kinase
- Ribosomal s6 kinase
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Tyrosine: |
- ZAP70
- Focal adhesion protein-tyrosine kinase
- BTK
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both |
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Other protein phosphatase |
Serine/threonine: |
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Tyrosine: |
- protein tyrosine phosphatase: Receptor-like protein tyrosine phosphatase
- Sh2 domain-containing protein tyrosine phosphatase
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both: |
- Dual-specificity phosphatase
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Apoptosis |
- see apoptosis signaling pathway
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GTP-binding protein regulators |
- see GTP-binding protein regulators
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Other |
- Activating transcription factor 6
- Signal transducing adaptor protein
- I-kappa B protein
- Mucin-4
- Olfactory marker protein
- Phosphatidylethanolamine binding protein
- EDARADD
- PRKCSH
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see also deficiencies of intracellular signaling peptides and proteins
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Esterase: protein tyrosine phosphatases (EC 3.1.3.48)
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Class I |
Classical PTPs |
Receptor type PTPs |
- PTPRA
- PTPRB
- PTPRC
- PTPRD
- PTPRE
- PTPRF
- PTPRG
- PTPRH
- PTPRJ
- PTPRK
- PTPRM
- PTPRN
- PTPRN2
- PTPRO
- PTPRQ
- PTPRR
- PTPRS
- PTPRT
- PTPRU
- PTPRZ1
- PTPRZ2
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Non receptor type PTPs |
- PTPN1
- PTPN2
- PTPN3
- PTPN4
- PTPN5
- PTPN6
- PTPN7
- PTPN9
- PTPN11
- PTPN12
- PTPN13
- PTPN14
- PTPN18
- PTPN20
- PTPN21
- PTPN22
- PTPN23
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VH1-like or
dual specific
phosphatases
(DSPs) |
MAPK phosphatases (MKPs) |
- DUSP1
- DUSP2
- DUSP4
- DUSP5
- DUSP6
- DUSP7
- DUSP8
- DUSP9
- DUSP10
- DUSP16
- MK-STYX
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Slingshots |
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PRLs |
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CDC14s |
- CDC14A
- CDC14B
- CDKN3
- PTP9Q22
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Atypical DSPs |
- DUSP3
- DUSP11
- DUSP12
- DUSP13A
- DUSP13B
- DUSP14
- DUSP15
- DUSP18
- DUSP19
- DUSP21
- DUSP22
- DUSP23
- DUSP24
- DUSP25
- DUSP26
- DUSP27
- EMP2A
- RNGTT
- STYX
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Phosphatase and tensin
homologs (PTENs) |
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Myotubularins |
- MTM1
- MTMR2
- MTMR3
- MTMR4
- MTMR5
- MTMR6
- MTMR7
- MTMR8
- MTMR9
- MTMR10
- MTMR11
- MTMR12
- MTMR13
- MTMR14
- MTMR15
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Class II |
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Class III |
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Class IV |
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