The β-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3 activation by binding to its nonconserved N terminus

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    Abstract

    The c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway mediates stress responses in cells. JNK activity is regulated by a protein kinase cascade consisting of a MAPK kinase (MKK) and a MAPK kinase kinase (MAPKKK). β-Arrestin-2 acts as a scaffold by directly binding to the JNK3 isoform and also by recruiting MKK4 and the MAPKKK apoptosis-signaling kinase-1 (ASK1). In this study, we demonstrate by co-precipitation that the extended N-terminal region of JNK3 mediates binding to the C terminus of β-arrestin-2 and that the N terminus of JNK3 is required for its activation via β-arrestin-2. We have used site-specific mutagenesis to identify key residues within the N terminus of JNK3 that are essential for binding and demonstrate that this region represents an independent β-arrestin-2 binding motif that can be fused to other MAPKs and permit their recruitment to the scaffold complex. In addition, we demonstrate that JNK3 recruits MKK4 to the β-arrestin-2 scaffold complex by binding to the MAPK docking domain (D-domain) located within the N terminus of MKK4. These findings uncover molecular determinants of β-arrestin-2 scaffold complex assembly and assign a previously unrecognized role for the unique extended N terminus of JNK3. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
    Original languageEnglish
    Pages (from-to)15903-15911
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume283
    Issue number23
    DOIs
    Publication statusPublished - 6 Jun 2008

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