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Chem Biol. 2005 Sep;12(9):981-91.

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

Author information

1
Department of Chemistry, University of Illinois, Chicago, 60607, USA.

Abstract

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.

PMID:
16183022
DOI:
10.1016/j.chembiol.2005.07.007
[Indexed for MEDLINE]
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