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Abstract
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-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-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.
Highlights
C-terminal fragment containing most of the TS-1 re- some ADAM family members, including TACE peats
Identification and Characterization of ADAM-TS12—To identify putative novel members of the ADAM family expressed in human tissues, we used the BLAST algorithm to scan the GenBankTM data base of ESTs looking for sequences with significant similarity to previously described family members
In this work we describe the finding of ADAM-TS12, a novel member of the ADAM-TS subfamily characterized by its complex pattern of thrombospondin domains and its restricted expression in normal human tissues
Summary
C-terminal fragment containing most of the TS-1 re- some ADAM family members, including TACE peats. This latter domain is followed by a C-terminal extension rich in cysteine residues that shows similarities with the C-terminal region of other ADAM-TSs. The additional domains present in ADAM-TS12 are the cause of the large size of this novel human disintegrin when compared with all remaining family members.
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