Abstract
Dual-specificity phosphatases (DSPs), which dephosphorylate proteins at Ser/Thr as well as Tyr residues, are thought to be involved in critical signaling events such as control of MAP kinases (MAPKs). We have isolated the cDNA for a novel DSP and termed it low molecular mass DSP-4 (LDP-4). LDP-4 is composed of 211 amino acids with a predicted molecular mass of 23.9-kDa. Northern blot analysis using various mouse tissues showed that the LDP-4 transcript was expressed exclusively in brain. In situ hybridization showed that brain expression of LDP-4 was ubiquitous except for the hippocampus. When expressed in COS-7 cells, FLAG-tagged LDP-4 protein was present within the nucleus and Golgi apparatus. LDP-4 expression did not reduce phosphorylation levels of MAPKs, but rather evoked activation of JNK and p38.
Similar content being viewed by others
References
Tonks NK, Neel BG (2001) Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol 13: 182–195
Camps M, Nichols A, Arkinstall S (2000) Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J 14: 6–16
Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410: 37–40
Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81: 807–869
Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, Arkinstall S (1998) The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J Biol Chem 273: 9323–9329
Todd JL, Tanner KG, Denu JM (1999) Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. J Biol Chem 274: 13271–13280
Alonso A, Saxena M, Williams S, Mustelin T (2001). Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem 276: 4766–4771
Marti F, Krause A, Post NH, Lyddane C, Dupont B, Sadelain M, King PD (2001) Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6. J Immunol 166: 197–206
Nakamura K, Tanoue K, Satoh T, Takekawa M, Watanabe M, Shima H, Kikuchi K (2002) A novel low-molecular-mass dual-specificity phosphatase, LDP-2, with a naturally occurring substitution that affects substrate specificity. J Biochem (Tokyo) 132: 463–470
Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M (2002) A novel dual specificity phosphatase SKRP1 interacts with the MAPK kinase MKK7 and inactivates the JNK MAPK pathway. Implication for the precise regulation of the particular MAPK pathway. J Biol Chem 277: 23909–23918
Chen AJ, Zhou G, Juan T, Colicos SM, Cannon JP, Cabriera-Hansen M, Meyer CF, Jurecic R, Copeland NG, Gilbert DJ, Jenkins NA, Fletcher F, Tan TH, Belmont JW (2002). The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway. J Biol Chem 277: 36592–36601
Shen Y, Luche R, Wei B, Gordon ML, Diltz CD, Tonks NK (2001) Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1. Proc Natl Acad Sci USA 98: 13613–13618
Zama T, Aoki R, Kamimoto T, Inoue K, Ikeda Y, Hagiwara M (2002) Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway. J Biol Chem 277: 23919–23926
Takagaki K, Satoh T, Tanuma N, Masuda K, Takekawa M, Shima H, Kikuchi K (2004) Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38. Biochem J 383: 447–455
Chomczynski P, Sacchi N (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162: 156–159
Nakamura K, Shima H, Watanabe M, Haneji T, Kikuchi K (1999) Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis. Biochem J 344 (Pt 3): 819–825
Yamasaki M, Yamada K, Furuya S, Mitoma J, Hirabayashi Y, Watanabe M (2001) 3-Phosphoglycerate dehydrogenase, a key enzyme for l-serine biosynthesis, is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia in the mouse brain. J Neurosci 21: 7691–7704
Bivona TG, Philips MR (2003). Ras pathway signaling on endomembranes. Curr Opin Cell Biol 15: 136–142
Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E (2004) Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell 7: 33–44
Harada T, Matsuzaki O, Hayashi H, Sugano S, Matsuda A, Nishida E (2003). AKRL1 and AKRL2 activate the JNK pathway. Genes Cells 8: 493–500
Yang DD, Kuan CY, Whitmarsh AJ, Rinocn M, Zheng TS, Davis RJ, Rakic P, Flavell RA (1997). Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389: 865–870
Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22: 667–676
Ross J, Armstead WM (2005). NOC/oFQ activates ERK and JNK but not p38 MAPK to impair prostaglandin cerebrovasodilation after brain injury. Brain Res 1054: 95–102
Acknowledgements
We thank Dr. J. M. Kryiakis for pMT-HA-p38α and Dr.␣M.␣Karin for pSRα-HA-JNK1 and pSRα-HA-ERK2. We are grateful to Mrs. E. Yoshida for secretarial assistance. This work was supported in part by HIROMI Medical Research Foundation, Osaka Cancer Research Foundation, grants-in-aid for Scientific Research (B) provided by the Japan Society for the Promotion of Science.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takagaki, K., Shima, H., Tanuma, N. et al. Characterization of a novel low-molecular-mass dual specificity phosphatase-4 (LDP-4) expressed in brain. Mol Cell Biochem 296, 177–184 (2007). https://doi.org/10.1007/s11010-006-9313-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-006-9313-5