Heat shock protein-90 dampens and directs signaling stimulated by insulin-like growth factor-1 and insulin.
Heat shock protein-90 (Hsp90) buffers cells from genetic mutations and environmental stresses. To test if this capability reflects a normal physiological function of Hsp90 to buffer cellular signals, the effects of Hsp90 inhibition were measured on activation of Akt. Inhibition of Hsp90 with geldanamycin amplified Akt phosphorylation induced by insulin-like growth factor-1 (IGF-1) or insulin, indicating that Hsp90 normally buffers these signals. Furthermore, with IGF-1 stimulation Hsp90 inhibition increased p38 activation, produced additive activation of p90RSK, and slightly increased the duration of ERK1/2 activation. Hsp90 dampened Akt signaling by facilitating phosphatase-mediated dephosphorylation of Akt. Thus, Hsp90 not only buffers the cellular effects of mutations and stresses, but also buffers the magnitude and duration of activation of proliferative and survival-promoting signaling responses.
Meares
Gordon P
GP
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, 1720 7th Ave South, Birmingham, AL 35294-0017, USA.
Zmijewska
Anna A
AA
Jope
Richard S
RS
D016227:Benzoquinones; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D047029:Lactams, Macrocyclic; D011809:Quinones / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007328:Insulin; D047029:Lactams, Macrocyclic; D011809:Quinones; D007334:Insulin-Like Growth Factor I; C001277:geldanamycin