A clickable inhibitor reveals context-dependent autoactivation of p90 RSK

Michael S. Cohen, Haralambos Hadjivassiliou, Jack Taunton

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

p90 ribosomal protein S6 kinases (RSKs) integrate upstream signals through two catalytic domains. Autophosphorylation of Ser386 by the regulatory C-terminal kinase domain (CTD) is thought to be essential for activation of the N-terminal kinase domain (NTD), which phosphorylates multiple downstream targets. We recently reported fmk, an irreversible inhibitor of the CTD of RSK1 and RSK2. Here we describe fmk-pa, a propargylamine variant that has improved cellular potency and a 'clickable' tag for assessing the extent and selectivity of covalent RSK modification. Copper-catalyzed conjugation of an azidoalkyl reporter (the click reaction) revealed that fmk-pa achieves selective and saturable modification of endogenous RSK1 and RSK2 in mammalian cells. Saturating concentrations of fmk-pa inhibited Ser386 phosphorylation and downstream signaling in response to phorbol ester stimulation, but had no effect on RSK activation by lipopolysaccharide. RSK autoactivation by the CTD is therefore context dependent, which suggests that NTD and CTD inhibitors should have distinct physiological effects.

Original languageEnglish (US)
Pages (from-to)156-160
Number of pages5
JournalNature Chemical Biology
Volume3
Issue number3
DOIs
StatePublished - Mar 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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