Geldanamycin anisimycins activate Rho and stimulate Rho- and ROCK-dependent actin stress fiber formation.
Heat shock protein 90 (Hsp90) is a member of the heat shock family of molecular chaperones that regulate protein conformation and activity. Hsp90 regulates multiple cell signaling pathways by controlling the abundance and activity of several important protein kinases and cell cycle-related proteins. In this report, we show that inhibition of Hsp90 by geldanamycin or its derivative, 17-allylamino-17-desmethoxygeldamycin, leads to activation of the Rho GTPase and a dramatic increase in actin stress fiber formation in human tumor cell lines. Inactivation of Rho prevents geldanamycin-induced actin reorganization. Hsp90 inactivation does not alter the appearance of filopodia or lamellipodia and tubulin architecture is not visibly perturbed. Our observations suggest that Hsp90 has an important and specific role in regulating Rho activity and Rho-dependent actin cytoskeleton remodeling.
Amiri
Anahita
A
Department of Biochemistry, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
Noei
Farahnaz
F
Feroz
Tahir
T
Lee
Jonathan M
JM
D000199:Actins / Q000187:drug effects / Q000502:physiology*; D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020690:GTPase-Activating Proteins / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
D000199:Actins; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C001277:geldanamycin