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.
Mitogen-activated protein (MAP) kinases can be grouped into three structural families, ERK, JNK, and p38, which are thought to carry out unique functions within cells. We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively. Here we characterize a new MAP kinase phosphatase, MKP-2, that is induced in human peripheral blood T cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. PAC1, MKP-2, and MKP-1 recognize ERK and p38, ERK and JNK, and ERK, p38, and JNK, respectively. Thus, individual MAP kinase phosphatases can differentially regulate the potential for cross-talk between the various MAP kinase pathways. A hyperactive allele of ERK2 (D319N), analogous to the Drosophila sevenmaker gain-of-function mutation, has significantly reduced sensitivity to all three MAP kinase phosphatases in vivo.
Chu
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Y
Labortory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Solski
P A
PA
Khosravi-Far
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R
Der
C J
CJ
Kelly
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K
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D029721:Drosophila Proteins; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D054637:Dual-Specificity Phosphatases; D004790:Enzyme Induction; D005260:Female; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014018:Tissue Distribution
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C517019:DUSP1 protein, human; C517032:DUSP2 protein, human; C490583:DUSP4 protein, human; D054638:Dual Specificity Phosphatase 1; D054641:Dual Specificity Phosphatase 2; D054637:Dual-Specificity Phosphatases; C517020:Dusp1 protein, mouse; C517033:Dusp2 protein, mouse; C517022:Mkp protein, Drosophila; D017027:Protein Tyrosine Phosphatases; D013755:Tetradecanoylphorbol Acetate