Heat shock protein 90 stabilization of ErbB2 expression is disrupted by ATP depletion in myocytes.
Heat shock protein (Hsp) 90 is a ubiquitously expressed chaperone that stabilizes expression of multiple signaling kinases involved in growth regulation, including ErbB2, Raf-1, and Akt. The chaperone activity of Hsp90 requires ATP, which binds with approximately 10-fold lower affinity than ADP. This suggests that Hsp90 may be a physiological ATP sensor, regulating the stability of growth signaling cascades in relation to cellular energy charge. Here we show that lowering ATP concentration by inhibiting glycolysis or mitochondrial respiration in isolated myocytes triggers rapid dissociation of Hsp90 from ErbB2 and degradation of ErbB2 along with other client proteins. The effect of disrupting Hsp90 chaperone activity by ATP depletion was similar to the effect of the pharmacological Hsp90 inhibitor geldanamycin. ATP depletion-induced disruption of Hsp90 chaperone activity was associated with cellular resistance to growth factor activation of intracellular signaling. ErbB2 degradation was also induced by the physiological stress of beta-adrenergic receptor stimulation in electrically stimulated cells. These results support a role for Hsp90 as an ATP sensor that modulates tissue growth factor responsiveness under metabolically stressed conditions and provide a novel mechanism by which cellular responsiveness to growth factor stimulation is modulated by cellular energy charge.
Peng
Xuyang
X
Whitaker Cardiovascular Institute and Center for Molecular Stress Response, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Guo
Xinxin
X
Borkan
Steven C
SC
Bharti
Ajit
A
Kuramochi
Yukio
Y
Calderwood
Stuart
S
Sawyer
Douglas B
DB
D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006019:Glycolysis; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic; D008024:Ligands; D008297:Male; D032342:Muscle Cells / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D011485:Protein Binding; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013997:Time Factors
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D011943:Receptors, Adrenergic, beta; C001277:geldanamycin