Heat shock protein 90 indirectly regulates ERK activity by affecting Raf protein metabolism.
Extracellular signal-regulated protein kinase (ERK) has been implicated in the pathogenesis of several nerve system diseases. As more and more kinases have been discovered to be the client proteins of the molecular chaperone Hsp90, the use of Hsp90 inhibitors to reduce abnormal kinase activity is a new treatment strategy for nerve system diseases. This study investigated the regulation of the ERK pathway by Hsp90. We showed that Hsp90 inhibitors reduce ERK phosphorylation without affecting the total ERK protein level. Further investigation showed that Raf, the upstream kinase in the Ras-Raf-MEK-ERK pathway, forms a complex with Hsp90 and Hsp70. Treating cells with Hsp90 inhibitors facilitates Raf degradation, thereby down-regulating the activity of ERK.
Department of Genetics and Development Biology, Southeast University Medical School, Nanjing 210009, China. feidou@yahoo.com.
Fei
F
Dou
Liu-Di
LD
Yuan
Jing-Jing
JJ
Zhu
D000818:Animals; D016227:Benzoquinones; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011809:Quinones; D014157:Transcription Factors; D016875:tau Proteins; D017828:Rifabutin; C112765:tanespimycin; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C001277:geldanamycin