Short Arrestin-3-Derived Peptides Activate JNK3 in Cells

• Published in: International journal of molecular sciences Vol. 23; no. 15; p. 8679
• Main Authors: Perry-Hauser, Nicole A., Kaoud, Tamer S., Stoy, Henriette, Zhan, Xuanzhi, Chen, Qiuyan, Dalby, Kevin N., Iverson, Tina M., Gurevich, Vsevolod V., Gurevich, Eugenia V.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2022; MDPI
• Subjects: Apoptosis; Arrestin; arrestin-3; Cell activation; G protein-coupled receptors; JNK; JNK3 protein; Kinases; Maltose; Maltose-binding protein; MAP kinase; Peptides; Protein kinase C; Proteins; scaffold; short peptides; Suppressors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23158679

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 JNK3α2 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.