Inhibition of peptidyl prolyl cis-trans isomerases decreases Crkii association with its functional binding partner in leukemic T cell Academic Article uri icon


  • Cell growth and differentiation are strictly controlled processes mediated by effector molecules, which are regulated by posttranslational chemical modifications. Adaptor proteins are critical players in these processes, thanks to their ability to simultaneously interact with two or more effector molecules and orchestrate the assembly of signaling complexes downstream of activated surface receptors. Among these adaptor proteins, CrkII is ubiquitously expressed, involved in multiple receptor-linked signaling pathways, and involved also in signal transduction downstream of activated T cell antigen receptors. Peptidyl prolyl cis-trans isomereses (PPIases) are widely distributed proteins and has recently emerged as important molecular timers in the dynamic regulation of biological processes. We aimed to determine whether CrkII can serve as an in vivo substrate for PPIases and whether inhibitors of PPIases can alter CrkII-dependent T cell activation responses. CrkII-based binding studies using PPIasesinhibitors treated or untreated T cells, a FRET-based assay, immunofluorescence assay by confocal microscopy and studies of the effect of the inhibitors on CrkII-dependent T cell functions, including cell adhesion and migration. Treatment of Jurkat T cells with the inhibitors decreased the ability of CrkII-SH3N domain to associate with binding partners. In parallel, this treatment altered the proportions of cis versus trans forms of CrkII, as indicated by FRET studies. Finally, CrkII overexpressioninduced increase of Jurkat T cell adherence and migration was significantly inhibited by pretreatment with PPIases-inhibitors.

publication date

  • September 1, 2012