Short Arrestin-3-Derived Peptides Activate JNK3 in Cells

Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate several signaling branches, including mitogen-activated protein kinase cascades. Arrestin-3-dependent activation of the JNK family can be recapitulated with peptide fragments, which are monofunctional elements distilled from this multi-functional arrestin protein. Here, we use maltose-binding protein fusions of arrestin-3-derived peptides to identify arrestin elements that bind kinases of the ASK1-MKK4/7-JNK3 cascade and the shortest peptide facilitating JNK signaling. We identified a 16-residue arrestin-3-derived peptide expressed as a Venus fusion that leads to activation of JNK3 alpha 2 in cells. The strength of the binding to the kinases does not correlate with peptide activity. The ASK1-MKK4/7-JNK3 cascade has been implicated in neuronal apoptosis. While inhibitors of MAP kinases exist, short peptides are the first small molecule tools that can activate MAP kinases.

Automated summary

Arrestins were initially identified as suppressors of G protein-mediated signaling, but they are also involved in initiating various signaling pathways, including the mitogen-activated protein kinase cascades. By studying peptide fragments derived from arrestin-3, a 16-residue peptide capable of activating JNK3 was identified, which provides a valuable tool for studying neuronal apoptosis.