RNA aptamers as pathway-specific MAP kinase inhibitors

Scott D. Seiwert*, Theresa Stines Nahreini, Stefan Aigner, Natalie G. Ahn, Olke C. Uhlenbeck

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Background: In eukaryotic cells, many intracellular signaling pathways have closely related mitogen activated protein kinase (MAPK) paralogs as central components. Although MAPKs are therefore obvious targets to control the cellular responses resulting from the activation of these signaling pathways, the development of inhibitors which target specific cell signaling pathways involving MAPKs has proven difficult. Results: We used an RNA combinatorial approach to isolate RNAs that inhibit the in vitro phosphorylation activity of extracellular regulated kinase 2 (ERK2). These inhibitors block phosphorylation by ERK1 and ERK2, but do not inhibit Jun N-terminal kinase or p38 MAPKs. Kinetic analysis indicates these inhibitors function at high picomolar concentrations through the steric exclusion of substrate and ATP binding. In one case, we identified a compact RNA structural domain responsible for inhibition. Conclusions: RNA reagents can selectively recognize and inhibit MAPKs involved in a single signal transduction pathway. The methodology described here is readily generalizable, and can be used to develop inhibitors of MAPKs involved in other signal transduction pathways. Such reagents may be valuable tools to analyze and distinguish homologous effectors which regulate distinct signaling responses.

Original languageEnglish (US)
Pages (from-to)833-843
Number of pages11
JournalChemistry and Biology
Volume7
Issue number11
DOIs
StatePublished - 2000

Keywords

  • Inhibitor
  • Kinase
  • Kinetics
  • Mitogen activated protein kinase
  • RNA aptamer
  • RNA selection

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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