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
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
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 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.
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.
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。
