Identification, Characterization, and Intracellular Processing of ADAM-TS12, a Novel Human Disintegrin with a Complex Structural Organization Involving Multiple Thrombospondin-1 Repeats

• Published in: The Journal of biological chemistry Vol. 276; no. 21; pp. 17932 - 17940
• Main Authors: Cal, Santiago, Argüelles, José M., Fernández, Pedro L., López-Otı́n, Carlos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-05-2001; American Society for Biochemistry and Molecular Biology
• Subjects: ADAM Proteins; ADAM-TS12 gene; ADAMTS Proteins; Amino Acid Sequence; Base Sequence; chromosome 5; Cloning, Molecular; Disintegrins - genetics; Disintegrins - metabolism; fetus; Humans; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Molecular Sequence Data; Protein Precursors - metabolism; Protein Processing, Post-Translational; Thrombospondins - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100534200

We have identified and cloned a human fetal lung cDNA encoding a new protein of the ADAM-TS family (adisintegrin 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-1 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-β 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.