MAP kinase phosphatases

Schaeffer HJ, Weber MJ: Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol. 1999, 19: 2435-3444. A review discussing how the regulation and localization of the MAP kinases, in conjunction with the participation of scaffold proteins and adapters, may determine different biological outcomes. Chang L, Karin M: Mammalian MAP kinase signalling cascades. Nature. 2001, 410: 37-40. 10.1038/35065000. A comprehensive review of mammalian MAP kinase signaling, focusing on the functions of the MAPK cascades. Marshall CJ: Specificity of receptor tyrosine kinase signalling: transient versus sustained extracellular signal regulated kinase activation. Cell. 1995, 80: 179-185. An excellent review on the role of the ERK MAP kinase pathway in differentiation and cell-fate determination: Marshall proposes that the duration of ERK activation is crucial in determining the biological outcome. Guan K, Broyles SS, Dixon JE: A Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature. 1991, 350: 359-362. 10.1038/350359a0. Cloning of VH1, the first member of the dual specificity phosphatase family. Demonstration that recombinant VH1 hydrolyzes substrates containing both phosphotyrosine and phosphoserine. Keyse SM, Ginsburg M: Amino acid sequence similarity between CL100, a dual-specificity MAP kinase phosphatase, and cdc25. Trends Biochem Sci. 1993, 18: 377-378. 10.1016/0968-0004(93)90092-2. Identification of two regions of amino-acid sequence similarity between the two phosphatases CL100 (DUSP1) and Cdc25. The authors propose a possible role for these regions in substrate interaction. Tanoue T, Adachi M, Moriguchi T, Nishida E: A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000, 2: 110-116. 10.1038/35000065. Identification of a docking site in ERK2, designated common docking domain, which is used in common for recognition and binding of its activators, substrates and regulators. A corresponding domain is also found in p38 and JNK/SAPK kinases. Wishart MJ, Dixon JE: Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains. Trends Biochem Sci. 1998, 23: 301-306. 10.1016/S0968-0004(98)01241-9. A comprehensive review of STYX domains. The authors present examples of several phosphatase-like proteins containing STYX domains and discuss their potential roles in mediating intracellular signaling. Noguchi T, Metz R, Chen L, Mattei M-G, Carrasco D, Bravo R: Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth. Mol Cell Biol. 1993, 13: 5195-5205. Structure and chromosomal localization of the murine erp gene (DUSP1). Stable expression of ERP in transfected NIH 3T3 fibroblasts resulted in growth inhibition and altered cell morphology. Kwak S, Hakes D, Martell K, Dixon JE: Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. J Biol Chem. 1994, 269: 3596-3604. Isolation of the human CL100 (DUSP1) gene, the characterization of its promoter and determination of the intron/exon boundaries. CL100 expression in discrete neuronal populations is also presented. Yi H, Morton CC, Weremowicz S, McBride OW, Kelly K: Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11. Genomics. 1995, 28: 92-96. 10.1006/geno.1995.1110. Structure and chromosomal localization of the human DUSP2 gene. Zhang T, Choy M, Jo M, Roberson MS: Structural organization of the rat mitogen-activated protein kinase phosphatase 2 gene. Gene. 2001, 273: 71-79. 10.1016/S0378-1119(01)00574-1. Genomic organization of the rat MKP-2 (DUSP4) gene, and characterization of its 5' untranslated region. Comparison of the structure of human MKP-1 (DUSP1) and rat MKP-2 genes. Dowd S, Sneddon AA, Keyse SM: Isolation of the human genes encoding the Pyst1 and Pyst2 phosphatases: characterization of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. J Cell Sci. 1998, 111: 3389-3399. Genomic organization of the human genes encoding the Pyst1 (DUSP6) and Pyst2 (DUSP7) phosphatases. The subcellular localization of Pyst2 protein is also determined. Nesbit MA, Hodges MD, Campbell L, de Meulemeester TM, Alders M, Rodrigues NR, Talbot K, Theodosiou AM, Mannens MA, Nakamura Y, et al: Genomic organization and chromosomal localization of a member of the MAP kinase phosphatase gene family to human chromosome 11p15.5 and a pseudogene to 10q11.2. Genomics. 1997, 42: 284-294. 10.1006/geno.1997.4737. Structure of human DUSP8 and its localization to chromosome 11p15.5. The authors also report the identification of a pseudogene on chromosome 10q11.2. Tanoue T, Yamamoto T, Maeda R, Nishida E: A novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38α and β MAPKs. J Biol Chem. 2001, 276: 26629-26639. 10.1074/jbc.M101981200. Identification and characterization of human MKP-7 (DUSP16), which shows substrate preference for JNK and p38. The authors also propose a tentative classification of MKPs based on the sequence characteristics of their MAP kinase-docking sites. Masuda K, Shima H, Watanabe M, Kikuchi K: MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001, 276: 39002-39011. 10.1074/jbc.M104600200. The authors present the cloning of human and mouse MKP-7 (DUSP16). They propose that this phosphatase also functions as a shuttle protein as it has both a nuclear export and a nuclear localization signal in its sequence. Doi K, Gartner A, Ammerer G, Errede B, Shinkawa H, Sugimoto K, Matsumoto K: MSG5, a novel protein phosphatase promotes adaptation to pheromone. EMBO J. 1994, 13: 61-70. Isolation of the phosphatase MSG5 as a suppressor of pheromone-stimulated G1 arrest in yeast cells. Loss of Msg5 function leads to increased activation of Fus3. These findings coupled with the in vitro dephosphorylation of Fus3 by Msg5 suggested a role for Msg5 in negative feedback control of MAP kinase signaling. Morrison DK, Murakami MS, Clephon V: Protein kinases and phosphatases in the Drosophila genome. J Cell Biol. 2000, 150: F57-F62. 10.1083/jcb.150.2.F57. A review of the kinases and phosphatases in the Drosophila genome. Provides an excellent link to a detailed table of all the genes identified in Drosophila. Martin-Blanco E, Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky AM, Martinez-Arias A: puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Genes Dev. 1998, 12: 557-570. The identification of puckered, encoding a Drosophila MKP homolog. Mutations in this gene led to cytoskeletal defects resulting in failure of dorsal closure. Martin-Blanco et al. demonstrate that this phosphatase mediates a feedback loop regulating JNK activity during Drosophila development. Kim S-H, Kwon H-B, Kim Y-S, Ryu J-H, Kim K-S, Ahn Y, Lee W-J, Choi K-Y: Isolation and characterization of a Drosophila homologue of mitogen-activated protein kinase phosphatase-3 which has a high substrate specificity towards extracellular-signal-regulated kinase. Biochem J. 2002, 361: 143-151. 10.1042/0264-6021:3610143. Characterization of Drosophila MKP-3 (DUSP6). When expressed in cultured Schneider cells, DMKP-3 inhibits DERK activity and binds with DERK via its amino-terminal domain. Plowman GD, Sudarsanam S, Bingham J, Whyte D, Hunter T: The protein kinases of Caenorhabditis elegans : a model for signal transduction in multicellular organisms. Proc Natl Acad Sci USA. 1999, 96: 13603-13610. 10.1073/pnas.96.24.13603. A comprehensive review of the kinase and phosphatase families identified in C. elegans. Berset T, Hoier EF, Battu G, Canevascini S, Hajnal A: Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science. 2001, 291: 1055-1058. 10.1126/science.1055642. Genetic dissection of the role of LIP-1 phosphatase during cell fate determination in vulval development in the worm. Ulm R, Revenkova E, di Sansebastiano G-P, Bechtold N, Paszkowski J: Mitogen-activated protein kinase phosphatase is required for genotoxic stress relief in Arabidopsis. Genes Dev. 2001, 15: 699-709. 10.1101/gad.192601. The identification of an Arabidopsis mutant that is hypersensitive to genotoxic stress treatments (UV-C and methyl methanesulphonate). This sensitivity is due to disruption of the gene AtMKP1, encoding an Arabidopsis MKP homolog, which is a key regulator of MAP kinase activity in vivo. Denu JM, Dixon JE: Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Curr Opin Chem Biol. 1998, 2: 633-641. 10.1016/S1367-5931(98)80095-1. This review outlines the common catalytic mechanism employed by protein tyrosine phosphatases and ways of regulating phosphatase activity. Stewart AE, Dowd S, Keyse SM, McDonald NQ: Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nat Struct Biol. 1999, 6: 174-181. 10.1038/5861. The crystal structure of the catalytic domain of Pyst1 (DUSP6). This reveals that in the absence of substrate the active site is distorted, suggesting that it undergoes conformational change upon ERK2 binding. Using site-directed mutagenesis Stewart et al. identify an aspartate that is essential for catalysis. Yuvaniyama J, Denu JM, Dixon JE, Saper MA: Crystal structure of the dual-specificity protein phosphatase VHR. Science. 1996, 272: 1328-1331. The authors determine the crystal structure of the human dual specificity phosphatase VHR, and show that it forms a shallow active-site cleft that allows for the hydrolysis of phosphoserine, phosphothreonine or phosphotyrosine residues. Chu Y, Solski PA, Khosravi-Far R, Der CJ, Kelly K: The mitogen-activated protein kinase phosphatases PAC1, MKP-1 and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem. 1996, 271: 6497-6501. 10.1074/jbc.271.11.6497. The authors demonstrate that the phosphatases PAC-1 (DUSP2), MKP-1 (DUSP1) and MKP-2 (DUSP4) show unique substrate specificities. PAC-1 is specific for ERK and p38, MKP-2 for JNK, and ERK and MKP-1 for p38 and JNK. All three phosphatases show reduced activity toward the ERK2 sevenmaker mutant. Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S: Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998, 280: 1262-1265. 10.1126/science.280.5367.1262. This paper shows that MKP-3 (DUSP6) is activated by direct binding to purified ERK2 and that this activation is specific to ERK2. Similarly, MKP-4 (DUSP9) is also activated by ERK2 binding. The authors suggest that this mechanism may underlie the substrate specificity of this group of enzymes. Todd JL, Tanner KG, Denu JM: Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. J Biol Chem. 1999, 274: 13271-13280. 10.1074/jbc.274.19.13271. Demonstration that immunodepletion of endogenous VHR eliminates the dephosphorylation of cellular ERK, suggesting that VHR specifically inactivates ERK in vivo. Alonso A, Saxena S, Williams S, Mustelin T: Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem. 2001, 276: 4766-4771. 10.1074/jbc.M006497200. Evidence that VHR, when expressed exogenously in Jurkat T cells, counteracts the Erk and Jnk MAP kinases and all reporter genes depending on them. The authors also show that catalytically inactive VHR behaves as a 'dominant negative' mutant. Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K: Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 1999, 13: 163-175. 10.1101/gad.13.20.2678. Suggestion that the FXFP motif is a docking site that mediates ERK binding to substrates in multiple protein families. The authors also identify another motif, designated D domain/box, that mediates binding to both ERK and JNK kinases. Their findings suggest that the overlapping substrate specificities of these kinases may result from recognition of shared or unique docking sites. Zhou B, Wu L, Shen K, Zhang J, Lawrence DS, Zhang Z-Y: Multiple regions of MAP kinase phosphatase 3 are involved in its recognition and activation by ERK2. J Biol Chem. 2001, 276: 6506-6515. 10.1074/jbc.M009753200. Using site-directed mutagenesis, three regions within the MKP-3 (DUSP6) sequence that are important for its binding to ERK2 are determined. In addition, the authors demonstrate that the FTAP motif in the carboxyl terminus of the phosphatase is absolutely essential for ERK2-induced MKP-3 activation. Fantz DA, Jacobs D, Glossip D, Kornfeld K: Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specific residues. J Biol Chem. 2001, 276: 27256-27265. 10.1074/jbc.M102512200. The paper focuses on the functions of the FXFP and D-domain docking sites. In addition to mediating ERK binding, these sites can direct phosphorylation on specific serine/threonine residues adjacent to proline residues. Yang S-H, Whitmarsh AJ, Davis RJ, Sharrocks AD: Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J. 1998, 17: 1740-1749. 10.1093/emboj/17.6.1740. Evidence that, in addition to the ERK MAP kinases, the JNKs are also targeted to Elk-1 by the D domain, and that this targeting is essential for phosphorylation and activation of Elk-1. Johnson TR, Biggs JR, Winbourn SE, Kraft AS: Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. J Biol Chem. 2000, 275: 31755-31762. 10.1074/jbc.M004182200. An examination of the regulation of M3/6/hVH-5 (DUSP8) in response to PMA treatment. Activation of JNK stimulates M3/6 phosphorylation and a delta-domain like motif in M3/6, the deletion of which inhibits the phosphatase activity of the enzyme, is identified. Rechsteiner M, Rogers SW: PEST sequences and regulation by proteolysis. Trends Biochem Sci. 1996, 21: 267-271. 10.1016/0968-0004(96)10031-1. This review focuses on the experimental evidence supporting the hypothesis that PEST sequences target proteins for rapid degradation, and on the mechanisms responsible for this degradation. Matsuguchi T, Musikacharoen T, Johnson TR, Kraft AS, Yoshikai Y: A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines. Mol Cell Biol. 2001, 21: 6999-7009. 10.1128/MCB.21.20.6999-7009.2001. Cloning of mouse MKP-M (mouse ortholog of DUSP16), a cytosolic MKP, which shows substrate specificity for JNK and p38. MKP-M is constitutively expressed in mouse macrophage cell lines with increased expression upon LPS stimulation. Fjeld CC, Rice AE, Kim Y, Gee KR, Denu JM: Mechanistic basis for catalytic activation of mitogen-activated protein kinase phosphatase-3 by extracellular signal-regulated kinase. J Biol Chem. 2000, 275: 6749-6757. 10.1074/jbc.275.10.6749. This paper provides biochemical evidence that ERK activates MKP-3 (DUSP6) through the stabilization of the active phosphatase conformation. Farooq A, Chaturvedi G, Mujtaba S, Plotnikova O, Zeng L, Dhalluin C, Ashton R, Zhou M-M: Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2. Mol Cell. 2001, 7: 387-399. The solution structure of the ERK2 binding domain of MKP-3 (DUSP6). The authors also use biochemical analysis and define regions within the amino terminus of MKP-3 that are used for binding ERK2 but also interact with the carboxy-terminal catalytic domain, and propose a mechanism for the catalytic activation of MKP-3. Chen P, Hutter D, Yang X, Gorospe M, Davis RJ, Liu Y: Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem. 2001, 276: 29440-29449. 10.1074/jbc.M103463200. The catalytic activity of recombinant MKP-2 (DUSP4) is enhanced by ERK1 and JNK1. The authors also show that MKP-2 binds preferentially to ERK and p38, and define the region of interaction within the amino-mutant. terminus of the phosphatase. Hutter D, Chen P, Barnes J, Liu Y: Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase: critical role of the p38 C-terminal domain in its negative regulation. Biochem J. 2000, 352: 155-163. 10.1042/0264-6021:3520155. MKP-1 (DUSP1) binds directly to p38 MAP kinase both in vitro and in vivo and this interaction results in the catalytic activation of MKP-1. Brondello J-M, Pouyssegur J, McKenzie FR: Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science. 1999, 286: 2514-2517. 10.1126/science.286.5449.2514. MKP-1 (DUSP1) is a labile protein and is targeted for proteosomal degradation via ubiquitination but phosphorylation of MKP-1 by ERK leads to the stabilization of the phosphatase. Rohan PJ, Davis P, Moskaluk CA, Kearns M, Krutzsch H, Siebenlist U, Kelly K: PAC-1: a mitogen-induced protein nuclear tyrosine phosphatase. Science. 1993, 259: 1763-1766. The PAC-1 (DUSP2) phosphatase, cloned from human T cells. PAC-1 is predominantly expressed in hematopoietic tissues and is localized to the nucleus. Martell KJ, Seasholtz AF, Kwak SP, Clemens KK, Dixon JE: hVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. J Neurochem. 1995, 65: 1823-1833. Isolation and characterization of human hVH-5 (DUSP8), which is abundant in brain. The expression pattern of hVH-5 in mouse embryos reveals abundant and wide distribution in the central and peripheral nervous system. Theodosiou AM, Rodrigues NR, Nesbit MA, Ambrose HJ, Paterson H, McLellan-Arnold E, Boyd Y, Leversha MA, Owen N, Blake DJ, et al: A member of the MAP kinase phosphatase gene family in mouse containing a complex trinucleotide repeat in the coding region. Hum Mol Genet. 1996, 5: 675-684. 10.1093/hmg/5.5.675. This paper describes the cloning and characterization of the mouse M3/6 (DUSP8) gene, which maps to distal mouse chromosome 7 and is predominantly expressed in brain. The subcellular localization of M3/6 is cell-type-dependent. Muda M, Boschert U, Smith A, Antonsson B, Gillieron C, Chabert C, Camps M, Martinou I, Ashworth A, Arkinstall S: Molecular cloning and functional characterization of a novel mitogen activated protein kinase phosphatase, MKP-4. J Biol Chem. 1997, 272: 5141-5151. 10.1074/jbc.272.8.5141. Human MKP-4 (DUSP9), a phosphatase that is highly selective for ERK, maps to human Xq28 and displays distinct subcellular localization. Theodosiou A, Smith A, Gillieron C, Arkinstall S, Ashworth A: MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases. Oncogene. 1999, 18: 6981-6988. 10.1038/sj/onc/1203185. Cloning of human MKP5 (DUSP10) and mapping to human chromosome 1q32. Demonstration that MKP5 preferentially binds to and inactivates the p38 and JNK kinases. Guan K-L, Butch E: Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J Biol Chem. 1995, 270: 7197-7203. 10.1074/jbc.270.13.7197. Isolation and characterization of human HVH2 (DUSP4), a nuclear MKP that shows substrate selectivity for ERK1 and ERK2. Kwak SP, Dixon JE: Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines. J Biol Chem. 1995, 270: 1156-1160. 10.1074/jbc.270.6.2431. Identification of human hVH-3 (DUSP5) and comparison of its levels of expression and tissue distribution to other known members of the family of MKPs. Groom LA, Sneddon AA, Alessi DR, Dowd S, Keyse SM: Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 1996, 15: 3621-3632. Identification of human Pyst1 (DUSP6) and Pyst2 (DUSP7). Pyst 1 is the first member of the MKPs that is localized exclusively in the cytoplasm,is not encoded by an immediate early gene and shows substrate specificity for ERK. Mourey RJ, Vega QC, Campbell JS, Wenderoth MP, Hauschka SD, Krebs EG, Dixon JE: A novel cytoplasmic dual specificity protein tyrosine phosphatase implicated in muscle and neuronal differentiation. J Biol Chem. 1996, 271: 3795-3802. 10.1074/jbc.271.7.3795. The cloning and characterization of rat rVH6 (DUSP6), a cytoplasmic MKP. The authors also show that in PC12 cells the expression of rVH6 is induced during nerve growth factor-mediated differentiation, whereas in muscle cells it is highly expressed during proliferation. Muda M, Boschert U, Dickinson R, Martinou J-C, Martinou I, Camps M, Schlegel W, Arkinstall S: MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem. 1996, 271: 4319-4326. 10.1074/jbc.271.8.4319. This paper describes the cloning and characterization of rat MKP-3 (DUSP6) and MKP-X (DUSP7), and shows that MKP-3 is a cytosolic MKP that specifically inactivates ERK. Expression studies of MKP-3 reveal that it is enriched within the CA1 layer of the hippocampus. Tanoue T, Moriguchi T, Nishida E: Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5. J Biol Chem. 1999, 274: 19949-19956. 10.1074/jbc.274.28.19949. Human MKP-5 (DUSP10), which shows substrate specificity for p38 and JNK, is localized in both the cytoplasm and the nucleus and its expression is induced by stress stimuli. Dorfman K, Carrasco D, Gruda M, Ryan C, Lira SA, Bravo R: Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene. 1996, 13: 925-931. MKP-1 (DUSP1) knockout mice show no phenotypic or histological abnormalities. Muda M, Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C, Davies K, Ashworth A, Arkinstall S: The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J Biol Chem. 1996, 271: 27205-27208. 10.1074/jbc.271.44.27205. Demonstration that M3/6 (DUSP8) displays high substrate specificity for JNK and p38 whereas MKP-3 (DUSP6) is highly selective for ERK MAP kinases. Hirsch DD, Stork PJS: Mitogen-activated protein kinase phosphatases inactivate stress-activated protein kinase pathways in vivo. J Biol Chem. 1997, 272: 4568-4575. 10.1074/jbc.272.7.4568. Examination of the ability of MKP-1 (DUSP1) and MKP-2 (DUSP4) to dephosphorylate JNK1 and JNK2. Both phosphatases are able to block the activation of c-Jun, and in PC12 cells they are both transcriptionally induced upon nerve growth factor (NGF) stimulation. Reffas S, Schlegel W: Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells. Biochem J. 2000, 352: 701-708. 10.1042/0264-6021:3520701. Regulation of MKP-1 (DUSP1) and MKP-3 (DUSP6) during induction of neuronal differentiation in mouse P19 cells. The authors demonstrate that the levels of the two phosphatases increase with different kinetics, in different cell compartments and through distinct pathways. Mansour SJ, Matten WT, Hermann AS, Candia JM, Rong S, Fukasawa K, Vande Woude GF, Ahn NG: Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994, 265: 966-970. Expression of constitutively active MAPKK mutants in cells results in activation of AP-1-regulated transcription and formation of transformed foci and tumors in nude mice. Cowley S, Paterson H, Kemp P, Marshall CJ: Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994, 77: 841-852. Constitutively active and interfering mutants of MAPKK1 are generated and their effects in PC12 and NIH 3T3 cells are assessed. In these cell lines, activation of MAPKK is necessary and sufficient for cell differentiation and proliferation, respectively. Webb CP, Van Aelst L, Wigler MH, Vande Woude GF: Signaling pathways in Ras mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA. 1998, 95: 8773-8778. 10.1073/pnas.95.15.8773. The tumorigenic and metastatic potential of effector domain mutants of oncogenic Ras is assessed. Keyse SM, Emslie EA: Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature. 1992, 359: 644-647. 10.1038/359644a0. Cloning of the first member of the MKPs, human CL100 (DUSP1). They demonstrate that it has phosphatase activity and show that it is induced by oxidative stress and heat shock. Charles CH, Abler AS, Lau LF: cDNA sequence of a growth factor-inducible immediate early gene and characterization of its encoded protein. Oncogene. 1992, 7: 187-190. The paper describes the isolation and characterization of the mouse 3CH134 (DUSP1) gene. Martell KJ, Kwak S, Hakes DJ, Dixon JE, Trent JM: Chromosomal localization of four human VH1-like protein-tyrosine phosphatases. Genomics. 1994, 22: 462-464. 10.1006/geno.1994.1411. The chromosomal localization of DUSP1, DUSP2 and DUSP5 genes. King AG, Ozanne BW, Smythe C, Ashworth A: Isolation and characterization of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. Oncogene. 1995, 11: 2553-2563. Isolation of TYP1 (DUSP4), a nuclear MKP that specifically inactivates ERK2 and JNK. Misra-Press A, Rim CS, Roberson MS, Stork PJS: A novel mitogen-activated protein kinase phosphatase. J Biol Chem. 1995, 270: 14587-14596. 10.1074/jbc.270.24.14587. Isolation and characterization of rat MKP-2 (DUSP4), mapping of its expression in the rat brain and demonstration that both NGF and epidermal growth factor (EGF) induce a rapid increase in MKP-2 mRNA levels. Smith A, Price C, Cullen M, Muda M, King A, Ozanne B, Arkinstall S, Ashworth A: Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7). Genomics. 1997, 42: 524-527. 10.1006/geno.1997.4756. Mapping the human phosphatases DUSP4, 6 and 7 to chromosomes 8p12-p11, 12q22-23 and 3p21, respectively. Ishibashi T, Bottaro DP, Michieli P, Kelley CA, Aaronson SA: A novel dual specificity phosphatase induced by serum stimulation and heat shock. J Biol Chem. 1994, 269: 29897-29902. Report of the isolation and characterization of human B23 (DUSP5). Demonstration that B23 displays substrate selectivity for ERK and that it is induced by serum stimulation and heat shock. Shin D-Y, Ishibashi T, Choi TS, Chung E, Chung IY, Aaronson SA, Bottaro DP: A novel human ERK phosphatase regulates H-ras and v-raf signal transduction. Oncogene. 1997, 14: 2633-2639. 10.1038/sj.onc.1201106. The paper describes the cloning of the human B59 (DUSP7) MKP. It also shows that cotransfection of NIH3T3 cells with B59 inhibits morphological transformation caused by H-ras and v-raf oncogenes. Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994, 22: 4673-4680. A widely used method for the alignment of multiple protein sequences.