A chemical inhibitor reveals the role of Raf kinase inhibitor protein in cell migration.
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.
Zhu
Shoutian
S
Department of Chemistry, University of Illinois, Chicago, 60607, USA.
Mc Henry
Kevin T
KT
Lane
William S
WS
Fenteany
Gabriel
G
D000727:Androgen-Binding Protein / Q000235:genetics / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048490:raf Kinases / Q000037:antagonists & inhibitors*
D000727:Androgen-Binding Protein; D017931:DNA Primers; D004791:Enzyme Inhibitors; D048490:raf Kinases