A chemical inhibitor reveals the role of Raf kinase inhibitor protein in cell migration

Chem Biol. 2005 Sep;12(9):981-91. doi: 10.1016/j.chembiol.2005.07.007.


Raf kinase inhibitor protein (RKIP) is a modulator of cell signaling that functions as an endogenous inhibitor of multiple kinases. We demonstrate here a positive role for RKIP in the regulation of cell locomotion. We discovered that RKIP is the relevant cellular target of locostatin, a cell migration inhibitor. Locostatin abrogates RKIP's ability to bind and inhibit Raf-1 kinase, and it acts by disrupting a protein-protein interaction, an uncommon mode of action for a small molecule. Small interfering RNA-mediated silencing of RKIP expression also reduces cell migration rate. Overexpression of RKIP converts epithelial cells to a highly migratory fibroblast-like phenotype, with dramatic reduction in the sensitivity of cells to locostatin. RKIP is therefore the compound's valid target and a key regulator of cell motility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgen-Binding Protein / genetics
  • Androgen-Binding Protein / physiology
  • Animals
  • Base Sequence
  • Cell Movement
  • Cells, Cultured
  • Cloning, Molecular
  • DNA Primers
  • Dogs
  • Enzyme Inhibitors / pharmacology*
  • raf Kinases / antagonists & inhibitors*


  • Androgen-Binding Protein
  • DNA Primers
  • Enzyme Inhibitors
  • raf Kinases