AIM:To determine if the cytotail of the principal sheddase tumor necrosis factor-α converting enzyme (TACE;ADAM17) controls protein ectodomain shedding.METHODS:Site-directed mutagenesis was performed to derive TACE v...AIM:To determine if the cytotail of the principal sheddase tumor necrosis factor-α converting enzyme (TACE;ADAM17) controls protein ectodomain shedding.METHODS:Site-directed mutagenesis was performed to derive TACE variants. The resulting TACE expression plasmids with amino acid substitutions in the extracel-lular,cysteine-rich disintegrin domain (CRD) and/or deleted cytotail,along with an expression vector for the enhanced green fluorescence protein were transfected into shedding-defective M1 mutants stably expressing transmembrane L-selectin or transforming growth factor (TGF)-α. The expression levels of the TACE substrates at the cell surface were determined by flow cytometry. RESULTS:Consistent with published data,a single point mutation (C600Y) in the CRD led to shedding defi-ciency. However,removal of the cytotail from the C600Y TACE variant partially restored ectodomain cleavage of TGF-α and L-selectin. Cytotail-deleted mutants with any other substituting amino acid residues in place of Cys600 displayed similar function compared with tail-less C600Y TACE.CONCLUSION:The cytotail plays an inhibitory role,which becomes evident when it is removed from an enzyme with another mutation that affects the enzyme function.展开更多
It has been many years since "the tumor necrosis factor-a-converting enzyme”,also known as ADAM17/TACE, was described as "the enzyme that does it all” because of its role in neurodegenerative diseases and ...It has been many years since "the tumor necrosis factor-a-converting enzyme”,also known as ADAM17/TACE, was described as "the enzyme that does it all” because of its role in neurodegenerative diseases and in several physiological processes including proteolysis, adhesion, intracellular signaling, migration and proliferation. ADAM17/TACE is an integral membrane protein that belongs to the disintegrin and metalloprotease (ADAM) family. Several years ago, Romero-Grimaldi et al.展开更多
去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿...去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附、凋亡、转移、增殖等生物学行为。纵观ADAM17的研究,在多种恶性肿瘤中呈高表达状态,且这种高表达状态与肿瘤侵润程度及转移情况相关。随着人们对ADAM17基础科学的研究不断深入,ADAM17的临床应用前景也正被不断开发,鉴于其在多种恶性肿瘤组织中高表达的情况,可将其作为许多肿瘤的诊断标志物、及判断其转移和预后情况。靶向药物的研究给恶性肿瘤患者带来了新的福音,利用EGFR为研究扳机点成功研制出许多靶向药物,在EGFR的配体释放环节,ADAM17尤为重要。本文总结了ADAM17在恶性肿瘤发展中的作用及其机制,对其在癌症治疗的应用前景进行展望。展开更多
基金Supported by Grants from the National Institutes of Health,No.AG029859 the National Center of the American Heart Association,No.0330335Nthe New Jersey Commission on Cancer Research(NJCCR703010)to Fan H
文摘AIM:To determine if the cytotail of the principal sheddase tumor necrosis factor-α converting enzyme (TACE;ADAM17) controls protein ectodomain shedding.METHODS:Site-directed mutagenesis was performed to derive TACE variants. The resulting TACE expression plasmids with amino acid substitutions in the extracel-lular,cysteine-rich disintegrin domain (CRD) and/or deleted cytotail,along with an expression vector for the enhanced green fluorescence protein were transfected into shedding-defective M1 mutants stably expressing transmembrane L-selectin or transforming growth factor (TGF)-α. The expression levels of the TACE substrates at the cell surface were determined by flow cytometry. RESULTS:Consistent with published data,a single point mutation (C600Y) in the CRD led to shedding defi-ciency. However,removal of the cytotail from the C600Y TACE variant partially restored ectodomain cleavage of TGF-α and L-selectin. Cytotail-deleted mutants with any other substituting amino acid residues in place of Cys600 displayed similar function compared with tail-less C600Y TACE.CONCLUSION:The cytotail plays an inhibitory role,which becomes evident when it is removed from an enzyme with another mutation that affects the enzyme function.
基金supported by the Spanish Consejería de Innovación,Ciencia y Empleo,Junta de Andalucía(P10CTS6639)Ministerio de Econmía y Competitividad(BFU 2015-6852-R,MINECO/FEDER)(both to CC)
文摘It has been many years since "the tumor necrosis factor-a-converting enzyme”,also known as ADAM17/TACE, was described as "the enzyme that does it all” because of its role in neurodegenerative diseases and in several physiological processes including proteolysis, adhesion, intracellular signaling, migration and proliferation. ADAM17/TACE is an integral membrane protein that belongs to the disintegrin and metalloprotease (ADAM) family. Several years ago, Romero-Grimaldi et al.
文摘去整合素-金属蛋白酶17(adisintegrin and metalloproteinase17,ADAM17)是近年来发现的金属蛋白酶解聚素(adisintegrinand metalloproteinase,ADAMs)家族成员之一,参与肿瘤发生发展的重要过程。去整合素-金属蛋白酶17(ADAM17)又称为肿瘤坏死因子转换酶(TACE),因此除了具有解聚素和金属蛋白酶的活性,还可以将没有活性的肿瘤坏死因子(TNF-α)从细胞膜上切割下来,并与其受体相结合,从而激活TNF-α下游的EGFR信号传导,此外还可以激活多条信号传导途径如Notch传导通路等,进而影响肿瘤细胞的粘附、凋亡、转移、增殖等生物学行为。纵观ADAM17的研究,在多种恶性肿瘤中呈高表达状态,且这种高表达状态与肿瘤侵润程度及转移情况相关。随着人们对ADAM17基础科学的研究不断深入,ADAM17的临床应用前景也正被不断开发,鉴于其在多种恶性肿瘤组织中高表达的情况,可将其作为许多肿瘤的诊断标志物、及判断其转移和预后情况。靶向药物的研究给恶性肿瘤患者带来了新的福音,利用EGFR为研究扳机点成功研制出许多靶向药物,在EGFR的配体释放环节,ADAM17尤为重要。本文总结了ADAM17在恶性肿瘤发展中的作用及其机制,对其在癌症治疗的应用前景进行展望。
