Molecular chaperones and protein kinase quality control.
The Hsp90-Cdc37 chaperone pair has special responsibility for folding of protein kinases. This function has made Hsp90 a target for new chemotherapeutic approaches, and several compounds are currently being tested for their ability to inhibit many different kinases simultaneously. Not all kinases are sensitive to these inhibitors, however, and this difference might depend on how each kinase interacts with Hsp90 and Cdc37 during folding of the nascent chain and thereafter. Indeed, several kinases require the persistent presence of both chaperones after initial folding and some of these kinases seem to be particularly sensitive to Hsp90 inhibitors. This requirement might relate to conformational changes that take place during the protein kinase activity cycle.
Caplan
Avrom J
AJ
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA. Avrom.Caplan@mssm.edu <Avrom.Caplan@mssm.edu>
Mandal
Atin K
AK
Theodoraki
Maria A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000502:physiology*; D018833:Chaperonins / Q000502:physiology*; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008322:Mammals / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000378:metabolism
D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D018833:Chaperonins; C001277:geldanamycin