Identification of the Critical Features of a Small Peptide Inhibitor of JNK Activity

Renae Barr, T.S. Kendrick, M.A. Bogoyevitch

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

The c-Jun N-terminal kinases (JNKs) are a subfamily of the mitogen-activated protein kinases (NLAPKs). Although progress in evaluating the functions of other MAPKs has been facilitated by the characterization of specific inhibitors, no JNK-directed inhibitor is commercially available. We have identified a 21-amino acid peptide inhibitor of activated JNKs, based on amino acids 143-163 of the JNK-binding domain (JBD) of the JNK scaffolding protein, JNK-interacting protein-1 (JIP-1). This peptide, I-JIP (Inhibitor of JNK-based on JIP-1), inhibited JNK activity in vitro toward recombinant c-Jun, Elk, and ATF2 up to 90%. A truncated I-JIP (TI-JIP), the C-terminal 11 amino acids of I-JIP, directly interacted with recombinant JNKs but not its substrates as shown by surface plasmon resonance analysis. Scanning alanine replacement within truncated I-JIP identified 4 residues (Arg-156, Pro-157, Leu-160, or Leu-162) as independently critical for inhibition. JBD peptide sequences from JIP-2 and JIP-3 shared these critical residues and accordingly were effective JNK inhibitors. In contrast, peptides based on the JBDs of ATF2 and c-Jun inhibited JNK activity by
Original languageEnglish
Pages (from-to)10987-10997
JournalJournal of Biological Chemistry
Volume277
Issue number13
DOIs
Publication statusPublished - 2002

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