title: Analysis of conformational determinants underlying HSP90-kinase interaction.
abstract: The role of HSP90 in stabilization of oncogenic tyrosine kinases made it an attractive therapeutic target for treating cancer but the molecular basis underlying the interaction between the HSP90 chaperone and client kinases is not elucidated yet. Using kinase inhibitors we show that the inactive conformation of ERBB2 does not interact with HSP90 chaperone and is thus not amenable to degradation upon HSP90 inhibitor treatment, while active ERBB2 kinase conformation promotes interaction with the HSP90 machinery and thus is degraded upon HSP90 inhibitor treatment. Interestingly, the kinase-chaperone interaction is disrupted in case of BCR-ABL and FLT3-ITD when bound to inhibitors irrespective of whether they block the kinase in an active or inactive conformation and thus our results indicate that the stability of the active kinase conformation varies between different kinases.
authors.affiliation: Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Kancha
authors.forename: Natalie
authors.initials: N
authors.lastname: Bartosch
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D016044:Fusion Proteins, bcr-abl; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; C508053:ERBB2 protein, human