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MAPK phosphatases (MKPs) are critical modulators of the innate immune response, and yet the mechanisms regulating their accumulation remain poorly understood. In the present studies, we investigated the role of post-translational modification in the accumulation of MKP-1 and MKP-2 in macrophages following LPS stimulation. We found that upon LPS stimulation, MKP-1 and MKP-2 accumulated with different kinetics: MKP-1 level peaked at ∼1 h, while MKP-2 levels continued to rise for at least 6 h. Accumulation of both MKP-1 and MKP-2 were attenuated by inhibition of the ERK cascade. Interestingly, p38 inhibition prior to LPS stimulation had little effect on MKP-1 and MKP-2 protein levels, but hindered their detection by an M-18 MKP-1 antibody. Studies of the epitope sequence recognized by the M-18 MKP-1 antibody revealed extensive phosphorylation of two serine residues in the C terminus of both MKP-1 and MKP-2 by the ERK pathway. Remarkably, the stability of both MKP-1 and MKP-2 was markedly decreased in macrophages in the presence of an ERK pathway inhibitor. Mutation of the two C-terminal serine residues in MKP-1 and MKP-2 to alanine decreased their half-lives, while mutating these residues to aspartate dramatically increased their half-lives. Deletion of the C terminus from MKP-1 and MKP-2 also considerably increased their stabilities. Surprisingly, enhanced stabilities of the MKP-1 and MKP-2 mutants were not associated with decreased ubiquitination. Degradation of both MKP-1 and MKP-2 was attenuated by proteasomal inhibitors. Our studies suggest that MKP-1 and MKP-2 stability is regulated by ERK-mediated phosphorylation through a degradation pathway independent of polyubiquitination.

Titel:	Post-translational regulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2 in macrophages following lipopolysaccharide stimulation: the role of the C termini of the phosphatases in determining their stability.
Autor/in / Beteiligte Person:	Crowell, S ; Wancket, LM ; Shakibi, Y ; Xu, P ; Xue, J ; Samavati, L ; Nelin, LD ; Liu, Y
Link:	Full Text Finder (Volltext)
Zeitschrift:	The Journal of biological chemistry, Jg. 289 (2014-10-17), Heft 42, S. 28753-64
Veröffentlichung:	2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology ; <i>Original Publication</i>: Baltimore, MD : American Society for Biochemistry and Molecular Biology, 2014
Medientyp:	academicJournal
ISSN:	1083-351X (electronic)
DOI:	10.1074/jbc.M114.591925
Schlagwort:	Alanine chemistry Animals Epitopes metabolism Gene Expression Regulation, Enzymologic HEK293 Cells Humans Lipopolysaccharides chemistry Mice Phosphorylation Proteasome Inhibitors chemistry Protein Conformation Protein Structure, Tertiary Ubiquitin metabolism p38 Mitogen-Activated Protein Kinases metabolism Dual Specificity Phosphatase 1 metabolism Dual-Specificity Phosphatases metabolism Macrophages enzymology Mitogen-Activated Protein Kinase Phosphatases metabolism Protein Processing, Post-Translational Protein Tyrosine Phosphatases metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [J Biol Chem] 2014 Oct 17; Vol. 289 (42), pp. 28753-64. <i>Date of Electronic Publication: </i>2014 Sep 09. MeSH Terms: Protein Processing, Post-Translational* ; Dual Specificity Phosphatase 1 / metabolism ; Dual-Specificity Phosphatases / metabolism ; Macrophages / enzymology ; Mitogen-Activated Protein Kinase Phosphatases / metabolism ; Protein Tyrosine Phosphatases / *metabolism ; Alanine / chemistry ; Animals ; Epitopes / metabolism ; Gene Expression Regulation, Enzymologic ; HEK293 Cells ; Humans ; Lipopolysaccharides / chemistry ; Mice ; Phosphorylation ; Proteasome Inhibitors / chemistry ; Protein Conformation ; Protein Structure, Tertiary ; Ubiquitin / metabolism ; p38 Mitogen-Activated Protein Kinases / metabolism References: EMBO J. 2003 Nov 3;22(21):5793-805. (PMID: 14592977) ; Science. 1999 Dec 24;286(5449):2514-7. (PMID: 10617468) ; Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2274-9. (PMID: 16461893) ; Nat Rev Immunol. 2013 Sep;13(9):679-92. (PMID: 23954936) ; Nat Rev Drug Discov. 2007 May;6(5):391-403. (PMID: 17473844) ; Front Biosci (Landmark Ed). 2009 Jan 01;14(3):847-71. (PMID: 19273104) ; Biochem J. 2000 Nov 15;352 Pt 1:155-63. (PMID: 11062068) ; Curr Opin Cell Biol. 2000 Apr;12(2):186-92. (PMID: 10712927) ; Chem Biol. 2012 Jan 27;19(1):140-54. (PMID: 22284361) ; Biochim Biophys Acta. 2014 Jan;1843(1):216-21. (PMID: 23684952) ; J Exp Med. 1990 Jul 1;172(1):391-4. (PMID: 2358784) ; J Immunol. 2006 Feb 1;176(3):1899-907. (PMID: 16424221) ; Free Radic Res. 1999 Oct;31(4):341-9. (PMID: 10517539) ; Protein Expr Purif. 2006 Apr;46(2):468-74. (PMID: 16256366) ; J Biol Chem. 2004 Dec 24;279(52):54023-31. (PMID: 15485842) ; Cell. 2000 Dec 22;103(7):1071-83. (PMID: 11163183) ; Cell. 1994 Jun 3;77(5):727-36. (PMID: 8205621) ; Mol Cell Biol. 1998 Sep;18(9):5178-88. (PMID: 9710602) ; J Immunol. 2002 Dec 1;169(11):6408-16. (PMID: 12444149) ; J Immunol. 2006 Dec 1;177(11):7497-504. (PMID: 17114416) ; Free Radic Biol Med. 2000 May 1;28(9):1328-37. (PMID: 10924852) ; Biochim Biophys Acta. 2008 Dec;1786(2):153-77. (PMID: 18558098) ; J Biol Chem. 2005 Mar 4;280(9):8101-8. (PMID: 15590669) ; Nat Immunol. 2006 Mar;7(3):274-83. (PMID: 16474395) ; PLoS Pathog. 2010 Nov 11;6(11):e1001192. (PMID: 21085614) ; Curr Opin Cell Biol. 1997 Apr;9(2):180-6. (PMID: 9069255) ; J Exp Med. 2006 Jan 23;203(1):131-40. (PMID: 16380513) ; Mol Biosyst. 2012 Jan;8(1):368-73. (PMID: 22027891) ; Cell Signal. 2000 Jan;12(1):1-13. (PMID: 10676842) ; J Biol Chem. 2001 Aug 3;276(31):29440-9. (PMID: 11387337) ; J Leukoc Biol. 2007 Apr;81(4):860-9. (PMID: 17289800) ; Nat Rev Immunol. 2007 Mar;7(3):202-12. (PMID: 17318231) ; J Biol Chem. 1996 Mar 15;271(11):6497-501. (PMID: 8626452) ; Biochem J. 2004 Feb 15;378(Pt 1):27-34. (PMID: 14670075) ; J Exp Med. 2006 Jan 23;203(1):15-20. (PMID: 16380512) ; Immunol Rev. 2003 Apr;192:131-42. (PMID: 12670401) ; J Organ Dysfunct. 2009 Jan;5(2):68-78. (PMID: 21566680) ; Am J Physiol Lung Cell Mol Physiol. 2012 Aug 1;303(3):L251-8. (PMID: 22683570) ; Infect Immun. 2010 Jun;78(6):2868-76. (PMID: 20351138) ; Curr Protoc Protein Sci. 2002 Nov;Chapter 14:14.5.1-14.5.11. (PMID: 18429222) ; Annu Rev Immunol. 2002;20:55-72. (PMID: 11861597) Grant Information: HL 75261 United States HL NHLBI NIH HHS; AI 57798 United States AI NIAID NIH HHS; R01 AI068956 United States AI NIAID NIH HHS; HL113508 United States HL NHLBI NIH HHS; R01 AI057798 United States AI NIAID NIH HHS; R01 HL075261 United States HL NHLBI NIH HHS; AI 68956 United States AI NIAID NIH HHS; R21 AI057798 United States AI NIAID NIH HHS; R01 HL113508 United States HL NHLBI NIH HHS; K01 OD010985 United States OD NIH HHS Contributed Indexing: Keywords: Lipopolysaccharide (LPS); MAP Kinase Phosphatase; Macrophage; Phosphorylation; Post-translational Modification (PTM); Protein Stability; Ubiquitylation (Ubiquitination) Substance Nomenclature: 0 (Epitopes) ; 0 (Lipopolysaccharides) ; 0 (Proteasome Inhibitors) ; 0 (Ubiquitin) ; EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) ; EC 3.1.3.16 (Mitogen-Activated Protein Kinase Phosphatases) ; EC 3.1.3.48 (DUSP1 protein, human) ; EC 3.1.3.48 (DUSP4 protein, human) ; EC 3.1.3.48 (Dual Specificity Phosphatase 1) ; EC 3.1.3.48 (Dual-Specificity Phosphatases) ; EC 3.1.3.48 (Dusp1 protein, mouse) ; EC 3.1.3.48 (MKP2 protein, mouse) ; EC 3.1.3.48 (Protein Tyrosine Phosphatases) ; OF5P57N2ZX (Alanine) Entry Date(s): Date Created: 20140911 Date Completed: 20141222 Latest Revision: 20240321 Update Code: 20240321 PubMed Central ID: PMC4200237

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Post-translational regulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2 in macrophages following lipopolysaccharide stimulation: the role of the C termini of the phosphatases in determining their stability.