Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats (Retracted Article)
Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats (Retracted Article)
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DOI：
10.1074/jbc.m100534200
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发表时间：
2001-05-25
影响因子：
4.8
通讯作者：
López-Otin, C
中科院分区：
文献类型：
--
作者：
Cal, S;Argüelles, JM;López-Otin, C
我们已经鉴定并克隆了一个人胎肺cDNA，编码一种新的ADAM-TS家族蛋白（一种去整合素和金属蛋白酶结构域，具有血小板反应素1型模块），称为ADAM-TS 12。该蛋白具有与其他家族成员相似的结构域组织，包括前肽和金属蛋白酶样结构域、去整合素样结构域和富含半胱氨酸的结构域。然而，TS重复序列的数量和组织相对于其他人类ADAM-TS是独特的。在该新的ADAM-TS中，共存在三组排列的八个TS-1重复。ADAM-TS 12的细胞内加工的分析表明，它是作为前体分子合成的，首先通过在弗林蛋白酶介导的过程中切割前结构域激活，随后加工成两个不同大小的片段：120 kDa的N-末端蛋白水解活性片段，含有金属蛋白酶和去整合素结构域，和83 kDa的C-末端片段，含有大部分的TS-1重复。体细胞杂交和辐射杂交定位实验表明，人类ADAM-TS 12基因定位于5 q35，该位置不同于迄今为止定位的所有ADAM基因。对成人和胎儿组织RNA的北方印迹分析表明，ADAM-TS 12转录物仅在胎儿肺中以显著水平检测到，而在任何其他分析的组织中均未检测到。此外，在胃癌和来自不同来源的肿瘤细胞系中检测到ADAM-TS 12转录物，其由KMST人成纤维细胞中的转化生长因子-β诱导。这些数据表明，ADAM-TS 12可能通过其蛋白水解活性或作为潜在参与调节细胞粘附的分子在胎儿发育期间或肿瘤过程中的肺细胞中发挥作用。
We have identified and cloned a human fetal lung cDNA encoding a new protein of the ADAM-TS family (a disintegrin and metalloproteinase domain, with thrombospondin type-1 modules) that has been called ADAM-TS12, This protein exhibits a domain organization similar to the remaining family members including a propeptide and metalloproteinase-like, disintegrin-like, and cysteine-rich domains. However, the number and organization of the TS repeats is unique with respect to other human ADAM-TSs. A total of eight TS-l repeats arranged in three groups are present in this novel ADAM-TS. Analysis of intracellular processing of ADAM-TS12 revealed that it is synthesized as a precursor molecule that is first activated by cleavage of the prodomain in a furin-mediated process and subsequently processed into two fragments of different size: a 120-kDa N-terminal proteolytically active fragment containing the metalloproteinase and disintegrin domains, and a 83-kDa C-terminal fragment containing most of the TS-1 repeats. Somatic cell hybrid and radiation hybrid mapping experiments showed that the human ADAM-TS12 gene maps to 5q35, a location that differs from all ADAM genes mapped to date. Northern blot analysis of RNAs from human adult and fetal tissues demonstrated that ADAM-TS12 transcripts are only detected at significant levels in fetal lung but not in any other analyzed tissues. In addition, ADAM-TS12 transcripts were detected in gastric carcinomas and in tumor cell lines from diverse sources, being induced by transforming growth factor-beta in KMST human fibroblasts, These data suggest that ADAM-TS12 may play roles in pulmonary cells during fetal development or in tumor processes through its proteolytic activity or as a molecule potentially involved in regulation of cell adhesion.