Radicicol Leads to Selective Depletion of Raf Kinase and Disrupts K-Ras-activated Aberrant Signaling Pathway

Shiro Soga, Takako Kozawa, Hiroaki Narumi, Shiro Akinaga, Kenji Irie, Kunihiro Matsumoto, Sreenath V. Sharma, Hirofumi Nakano, Tamio Mizukami, Mitsunobu Hara
1998 Journal of Biological Chemistry  
Activation of Ras leads to the constitutive activation of a downstream phosphorylation cascade comprised of Raf-1, mitogen-activated protein kinase (MAPK) kinase, and MAPK. We have developed a yeast-based assay in which the Saccharomyces cerevisiae mating pheromoneinduced MAPK pathway relied on co-expression of K-Ras and Raf-1. Radicicol, an antifungal antibiotic, was found to inhibit the K-ras signaling pathway reconstituted in yeast. In K-ras-transformed, rat epithelial, and K-ras-activated,
more » ... uman pancreatic carcinoma cell lines, radicicol inhibited K-Ras-induced hyperphosphorylation of Erk2. In addition, the level of Raf kinase was significantly decreased in radicicol-treated cells, whereas the levels of K-Ras and MAPK remained unchanged. These results suggest that radicicol disrupts the K-Rasactivated signaling pathway by selectively depleting Raf kinase and raises the possibility that pharmacological destabilization of Raf kinase could be a new and powerful approach for the treatment of K-ras-activated human cancers. . 1 The abbreviations used are: MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MEK, same protein as MAPK kinase; Erk, extracellular signal-regulated protein kinase (same protein as MAP kinase); hsp90, heat shock protein 90; GAP, GTPase-activating protein.
doi:10.1074/jbc.273.2.822 pmid:9422737 fatcat:tidhcbdgxjdqpjq6wo5x5nmo3q