Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.
Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.
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作者：
小分子诱导的突变型Bcr-β 1降解为克服Bcr-β 1酪氨酸激酶抑制剂（TKI）耐药的慢性髓细胞白血病（CML）提供了一种潜在的方法。我们先前的研究报告，合成的甾体糖苷SBF-1通过诱导天然Bcr-11蛋白的降解显示出显著的抗CML活性。在这里，我们观察到SBF-1在携带T315 I突变Bcr-11的CML细胞中的体外和体内生长抑制相当。SBF-1通过破坏蛋白酪氨酸磷酸酶1B（PTP 1B）和Bcr-β 1之间的相互作用引发其降解。使用SBF-1作为工具，我们发现PTP 1B催化结构域中的Tyr 46和Bcr-1B 1 pleckstrin-同源（PH）结构域中的Tyr 852对于它们的相互作用至关重要。此外，Bcr-β 1 SH 2结构域中Tyr 1086的磷酸化募集E3泛素连接酶c-Cbl催化K27连接的泛素链，这是p62依赖性自噬降解的识别信号。PTP 1B在Tyr 1086处使Bcr-101去磷酸化，并阻止c-Cbl的募集，导致Bcr-101的稳定性。本研究揭示了PTP 1B稳定Bcr‐ Bcr‐ Bcr 1蛋白的作用机制，并表明PTP 1B ‐Bcr‐Bcr‐ Bcr 1相互作用可能是TKI耐药CML点突变的药物靶点之一。一种合成的甾体糖苷SBF-1可以通过破坏PTP 1B和Bcr-11之间的相互作用来触发T315 I突变型Bcr-11蛋白的降解，并克服TKI耐药的CML。使用SBF-1作为工具，我们确定了相互作用的关键氨基酸，并揭示了PTP 1B在稳定Bcr-1蛋白中的作用机制。
Small‐molecule‐induced degradation of mutant Bcr‐Abl1 provides a potential approach to overcome Bcr‐Abl1 tyrosine kinase inhibitor (TKI)‐resistant chronic myeloid leukemia (CML). Our previous study reported that a synthetic steroidal glycoside SBF‐1 showed remarkable anti‐CML activity by inducing the degradation of native Bcr‐Abl1 protein. Here, we observed the comparable growth inhibition for SBF‐1 in CML cells harboring T315I mutant Bcr‐Abl1 in vitro and in vivo. SBF‐1 triggered its degradation through disrupting the interaction between protein‐tyrosine phosphatase 1B (PTP1B) and Bcr‐Abl1. Using SBF‐1 as a tool, we found that Tyr46 in the PTP1B catalytic domain and Tyr852 in the Bcr‐Abl1 pleckstrin‐homology (PH) domain are critical for their interaction. Moreover, the phosphorylation of Tyr1086 within the Bcr‐Abl1 SH2 domain recruited the E3 ubiquitin ligase c‐Cbl to catalyze K27‐linked ubiquitin chains, which serve as a recognition signal for p62‐dependent autophagic degradation. PTP1B dephosphorylated Bcr‐Abl1 at Tyr1086 and prevented the recruitment of c‐Cbl, leading to the stability of Bcr‐Abl1. This study unravels the action mechanism of PTP1B in stabilizing Bcr‐Abl1 protein and indicates that the PTP1B‐Bcr‐Abl1 interaction might be one of druggable targets for TKI‐resistant CML with point mutations. A synthetic steroidal glycoside SBF‐1 could trigger the degradation of T315I mutant Bcr‐Abl1 protein via disrupting the interaction between PTP1B and Bcr‐Abl1, and overcome TKI‐resistant CML. Using SBF‐1 as a tool, we identified the amino acids crucial for the interaction and unraveled the action mechanism of PTP1B in stabilizing Bcr‐Abl1 protein.
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影响因子：
4.6
作者：
Shibata N;Shimokawa K;Nagai K;Ohoka N;Hattori T;Miyamoto N;Ujikawa O;Sameshima T;Nara H;Cho N;Naito M
通讯作者：
Naito M
DOI：
10.1056/nejmoa1609324
发表时间：
2017-03-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hochhaus A;Larson RA;Guilhot F;Radich JP;Branford S;Hughes TP;Baccarani M;Deininger MW;Cervantes F;Fujihara S;Ortmann CE;Menssen HD;Kantarjian H;O'Brien SG;Druker BJ;IRIS Investigators
通讯作者：
IRIS Investigators
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影响因子：
9
作者：
Gao J;Fan M;Xiang G;Wang J;Zhang X;Guo W;Wu X;Sun Y;Gu Y;Ge H;Tan R;Qiu H;Shen Y;Xu Q
通讯作者：
Xu Q
影响因子：
5.7
作者：
Shibata N;Miyamoto N;Nagai K;Shimokawa K;Sameshima T;Ohoka N;Hattori T;Imaeda Y;Nara H;Cho N;Naito M
通讯作者：
Naito M
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.