Identification and characterization of peptidyl-prolyl isomerase Pin1 as a new regulatory component of BCR::ABL1 degradation.

While tyrosine kinase inhibitors (TKIs) can effectively counteract BCR::ABL1 activity, resistance by BCR::ABL1 overexpression is a significant challenge in combating chronic myeloid leukemia, making down-regulation of BCR::ABL1 a promising anti-cancer strategy. We previously reported that the ubiquitin ligases c-Cbl and CHIP mediate BCR::ABL1 protein degradation. Bag1, a nucleotide exchange factor for Hsc70, senses immature structures of Hsp90-unchaperoned BCR::ABL1 protein and stimulates CHIP-induced BCR::ABL1 degradation. Peptidyl-prolyl cis/trans isomerases (PPIases) have been shown to regulate protein conformations for stability and degradation, while nothing is known about the PPIases for BCR::ABL1. Here we identified the parvulin-type Pin1 as a new regulatory component of BCR::ABL1 degradation system. Among several PPIases tested, we found that Pin1 specifically binds to BCR::ABL1 protein for degradation. Using a series of BCR::ABL1 mutants, we identified the SH2-binding domain of BCR portion as the Pin1 binding region. The Pin1 WW domain appears to associate with the one or more S/T-Pro motif(s) in the SH2 binding region of BCR::ABL1. Pin1 stimulates not only Hsp90 inhibitor- but also PP2A-induced protein degradation. We also found that Pin1 effectively inhibited TKI-induced BCR::ABL1 stabilization. Pin1 may convert the mature form BCR::ABL1 to an immature form for Bag1 recognition leading to CHIP-mediated ubiquitination and degradation. These findings may lead to provide a molecular basis for the development of new Pin1 related therapeutic strategies against TKI resistance.