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

doi:10.1128/MCB.21.20.6999-7009.2001

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Molecular and Cellular Biology, October 2001, p. 6999-7009, Vol. 21, No. 20
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.20.6999-7009.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Tetsuya Matsuguchi,¹^,^* Tipayaratn Musikacharoen,¹ Thomas R. Johnson,² Andrew S. Kraft,² and Yasunobu Yoshikai¹

Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya 466-8550, Japan,¹ and Department of Medical Oncology, University of Colorado Health Science Center, Denver, Colorado 80262²

Received 27 February 2001/Returned for modification 30 March 2001/Accepted 26 June 2001

We have isolated a cDNA homologous to known dual-specificity phosphatases from a mouse macrophage cDNA library and termedit MKP-M (for mitogen-activated protein kinase phosphatase isolatedfrom macrophages). Three other presumed splice variant isoformshave also been identified for MKP-M. The longest and most abundantmRNA contains an open reading frame corresponding to 677 aminoacids and produces an 80-kDa protein. The deduced amino acid sequenceof MKP-M is most similar to those of hVH-5 (or mouse M3/6) andVHP1, a Caenorhabditis elegans tyrosine phosphatase. It includesan N-terminal rhodanase homology domain, the extended active-sitesequence motif (V/L)X(V/I)HCXAG(I/V)SRSXT(I/V)XXAY(L/I)M (whereX is any amino acid), and a C-terminal PEST sequence. Northernblot analysis revealed a dominant MKP-M mRNA species of approximately5.5 kb detected ubiquitously among all tissues examined. MKP-Mwas constitutively expressed in mouse macrophage cell lines, andits expression levels were rapidly increased by lipopolysaccharide(LPS) stimulation but not by tumor necrosis factor alpha (TNF- $alpha$ ),gamma interferon, interleukin-2 (IL-2), or IL-15 stimulation.Immunocytochemical analysis showed MKP-M to be present withincytosol. When expressed in COS7 cells, MKP-M blocks activationof mitogen-activated protein kinases with the selectivity c-JunN-terminal kinase (JNK) p38 = extracellular signal-regulatedkinase. Furthermore, expression of a catalytically inactive formof MKP-M in a mouse macrophage cell line increased the intensityand duration of JNK activation and TNF- $alpha$ secretion after LPS stimulation,suggesting that MKP-M is at least partially responsible for thedesensitization of LPS-mediated JNK activation and cytokine secretioninmacrophages.

^* Corresponding author. Mailing address: Laboratory of Host Defense and Germfree Life, Research Institute for Disease Mechanismand Control, Nagoya University School of Medicine, 65 Tsurumai-cho,Showa-ku, Nagoya 466-8550, Japan. Phone: (052) 744-2447. Fax:(052) 744-2449. E-mail: tmatsugu{at}med.nagoya-u.ac.jp.

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