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PMID: 12788955 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates.

The Journal of biological chemistry ·Vol. 278 ·No. 35 ·2003-08-29 ·Pages 32662-72

Ho DT, Bardwell AJ, Abdollahi M, Bardwell L

Abstract

Specific docking interactions between MAPKs and their activating MAPK kinases (MKKs or MEKs) are crucial for efficient and accurate signal transmission. Here, we report the identification of a MAPK-docking site, or "D-site," in the N terminus of human MKK4/JNKK1. This docking site conforms to the consensus sequence for known D-sites in other MKKs and contains the first of the two cleavage sites for anthrax lethal factor protease that have been found in the N terminus of MKK4. This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38 alpha, and p38 beta to MKK4. Mutations that altered conserved residues in this docking site reduced JNK/p38 binding. In addition, a peptide version of this docking site, as well as a peptide version of the JNK-binding site of the JIP-1 scaffold protein, inhibited both MKK4/JNK binding and MKK4-mediated phosphorylation of JNK1. These same peptides also inhibited JNK2-mediated phosphorylation of c-Jun and ATF2, suggesting that transcription factors, MKK4, and the JIP scaffold compete for docking to JNK. Finally, the selectivity of the MKK4, MEK1, and MEK2 D-sites for JNK versus ERK was quantified. The MEK1 and MEK2 D-sites displayed a strong selectivity for their cognate MAPK (ERK2) versus a non-cognate MAPK (JNK). In contrast, the MKK4 D-site exhibited only limited selectivity for JNK versus ERK.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Binding Sites Codon Conserved Sequence DNA Primers/pharmacology Dose-Response Relationship, Drug Glutathione Transferase/metabolism Humans Kinetics MAP Kinase Kinase 4 MAP Kinase Signaling System Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 10 Mitogen-Activated Protein Kinase 11 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinase Kinases/chemistry,metabolism Mitogen-Activated Protein Kinases/metabolism Molecular Sequence Data Peptides/chemistry Phosphorylation Plasmids/metabolism Protein Binding Protein Biosynthesis Protein Structure, Tertiary Protein-Tyrosine Kinases/metabolism Recombinant Fusion Proteins/metabolism Transcription, Genetic p38 Mitogen-Activated Protein Kinases
Chemicals
Codon DNA Primers Peptides Recombinant Fusion Proteins Glutathione Transferase Mitogen-Activated Protein Kinase 10 Mitogen-Activated Protein Kinase 9 Protein-Tyrosine Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 11 Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase 4 MAP2K4 protein, human Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ho David T
Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
Bardwell A Jane
Abdollahi Mahsa
Bardwell Lee
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M304229200
Published
2003-08-29
Epub
2003-00-03
Pages
32662-72
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3017503
Subset
IM
Grants
NIGMS NIH HHS · R01 GM060366-04 · United States
NIGMS NIH HHS · GM60366 · United States
NIGMS NIH HHS · R01 GM060366 · United States
NLM NIH HHS · LM07443 · United States
NLM NIH HHS · T15 LM007443 · United States
External Links
PubMed source DOI: 10.1074/jbc.M304229200 PMC Full Text View journal details
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