Imatinib blocks tyrosine phosphorylation of Smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia  

作　　者：Lijing Wang Shuchen Gu Fenfang Chen Yi Yu Jin Cao Xinran Li Chun Gao Yanzhen Chen Shuchong Yuan Xia Liu Jun Qin Bin Zhao Pinglong Xu Tingbo Liang Hongyan Tong Xia Lin Xin-Hua Feng 

机构地区：[1]The MOE Key Laboratory of Biosystems Homeostasis&Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology,Life Sciences Institute,Zhejiang University,Hangzhou,Zhejiang 310058,China [2]Center for Life Sciences,Shaoxing Institute,Zhejiang University,Shaoxing,Zhejiang 321000,China [3]Cancer Center,Zhejiang University,Hangzhou,Zhejiang 310058,China [4]ZJU-Hangzhou Global Scientific and Technological Innovation Center,Zhejiang University,Hangzhou,Zhejiang 311200,China [5]Department of Hematology,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [6]Beijing Proteome Research Center,National Center for Protein Sciences,Beijing,China [7]Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [8]The Second Affiliated Hospital,Zhejiang University,Hangzhou,Zhejiang 310009,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1993-2006,共14页信号转导与靶向治疗（英文）

基　　金：grants from NSFC(U21A20356,31730057,and 91540205)and ZNSF(LD21C070001);the Fundamental Research Funds for the Central Universities.L.W.was supported by a short-term predoctoral fellowship from the Graduate School of Zhejiang University for studying abroad.

摘　　要：Loss of TGF-β-mediated growth suppression is a major contributor to the development of cancers,best exemplified by loss-offunction mutations in genes encoding components of the TGF-βsignaling pathway in colorectal and pancreatic cancers.Alternatively,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-βsignaling.However,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively investigated.Here,we show that the oncogenic BCR-ABL1 of chronic myelogenous leukemia(CML)and the cellular ABL1 tyrosine kinases phosphorylate and inactivate Smad4 to block antiproliferative TGF-βsignaling.Mechanistically,phosphorylation of Smad4 at Tyr195,Tyr301,and Tyr322 in the linker region interferes with its binding to the transcription co-activator p300/CBP,thereby blocking the ability of Smad4 to activate the expression of cyclin-dependent kinase(CDK)inhibitors and induce cell cycle arrest.In contrast,the inhibition of BCR-ABL1 kinase with Imatinib prevented Smad4 tyrosine phosphorylation and re-sensitized CML cells to TGF-β-induced antiproliferative and pro-apoptotic responses.Furthermore,expression of phosphorylation-site-mutated Y195F/Y301F/Y322F mutant of Smad4 in Smad4-null CML cells enhanced antiproliferative responses to TGF-β,whereas the phosphorylation-mimicking Y195E/Y301E/Y322E mutant interfered with TGF-βsignaling and enhanced the in vivo growth of CML cells.These findings demonstrate the direct role of BCR-ABL1 tyrosine kinase in suppressing TGF-βsignaling in CML and explain how Imatinib-targeted therapy restored beneficial TGF-βanti-growth responses.

关 键 词：SMAD4 PHOSPHORYLATION thereby 

分 类 号：R733.7[医药卫生—肿瘤]