NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

查看全文 作　　者：Ran [1,2]Wei;Xuguang [1]Liu;Courtney [1]Voss;Wentao [1]Qin;Lina [3]Dagnino;Lei [4]Li;Marc [5]Vigny;Shawn Shun-Cheng [1,6]Li

机构地区：[1]Departments of Biochemistry,Schulich School of Medicine and Dentistry,Western University,London,Ontario,N6A 5C1,Canada;[2]Dentistry,Schulich School of Medicine and Dentistry,Western University,London,Ontario,N6A 5C1,Canada;[3]Physiology and Pharmacology and Schulich School of Medicine and Dentistry,Western University,London,Ontario,N6A 5C1,Canada;[4]School of Basic Medical Sciences,Qingdao University,Qingdao 266021,Shandong,China;[5]Universite Pierre et Marie Curie,UPMC,INSERM UMRS-839,Paris,France;[6]Oncology,Schulich School of Medicine and Dentistry,Western University,London,Ontario,N6A 5C1,Canada

出　　处：《Journal of Molecular Cell Biology》索引2019年第11卷第11期,共12页

基　　金：grants(to S.S.-C.L.)from the Canadian Institutes of Health Research(CIHR)and the Canadian Cancer Society Research Institute.S.S.-C.L held a Canada Research Chair(Tier I)in Molecular and Epigenetic Basis of Cancer.R.W.and X.L.were recipients of Translational Breast Cancer Research Studentship from the Breast Cancer Society of Canada.R.W.received a studentship from the Schulich Dentistry Research Opportunity Program(SDROP).L.L.held a Shandong Provincial Natural Science Foundation grant and was a recipient of Distinguished Expert of Overseas Tai Shan Scholar. 摘　　要：NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion,migration,polarity,and cell fate determination.It has also been shown to play a role in the pathogenesis of certain cancers,although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor.Here,we show that NUMB binds to anaplastic lymphoma kinase(ALK),a receptor tyrosine kinase aberrantly activated in several forms of cancer,and this interaction regulates the endocytosis and activity of ALK.Intriguingly,the function of the NUMB-ALK interaction is isoform-dependent.While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK,the former directs ALK to the lysosomal degradation pathway,thus decreasing the overall ALK level and the downstream MAP kinase signal.In contrast,the p72-NUMB isoform promotes ALK recycling back to the plasma membrane,thereby maintaining the kinase in its active state.Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation. 关键词：ALK NUMB ISOFORM ENDOCYTOSIS degradation RECYCLING

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NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

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