Imatinib blocks tyrosine phosphorylation of Smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia
作者机构：The MOE Key Laboratory of Biosystems Homeostasis&Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell BiologyLife Sciences InstituteZhejiang UniversityHangzhouZhejiang 310058China Center for Life SciencesShaoxing InstituteZhejiang UniversityShaoxingZhejiang 321000China Cancer CenterZhejiang UniversityHangzhouZhejiang 310058China ZJU-Hangzhou Global Scientific and Technological Innovation CenterZhejiang UniversityHangzhouZhejiang 311200China Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Beijing Proteome Research CenterNational Center for Protein SciencesBeijingChina Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic DiseaseThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China The Second Affiliated HospitalZhejiang UniversityHangzhouZhejiang 310009China
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2023年第8卷第4期
页 面：1993-2006页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
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
主 题：Smad4 phosphorylation thereby
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 ***,gain-of-function oncogene mutations can also disrupt antiproliferative TGF-β***,the molecular mechanisms underlying oncogene-induced modulation of TGF-βsignaling have not been extensively ***,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-β***,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 *** 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 ***,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 *** 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.
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