Schematic representation of regulation of molecular fate of BCR-ABL by CHIP and c-Cbl. Newly synthesized BCR-ABL proteins are initially stabilized by Hsc70 and then passed on to Hsp90 and cdc37 to achieve maturation or kinase activation. c-Cbl induces ubiquitination-mediated degradation of mature BCR-ABL in a phosphorylation-dependent manner. Bag1 facilitates Hsc70-mediated folding of BCR-ABL. A large and multidomain protein such as BCR-ABL is inefficiently amenable to Hsc70-mediated folding. Bag1 recognizes immature BCR-ABL via BCR 1-413 and the ABL kinase domain, which is competed by Hsc70. CHIP acts not only as an E3 ligase for both immature BCR-ABL and Bag1 but also as a negative regulator of Hsc70 to promote the interaction of Bag1 and immature BCR-ABL. Bag1 binds to the proteasome and stimulates CHIP-induced BCR-ABL degradation. The mechanism can also apply to BCR-ABL degradation by Hsp90 inhibitors.