Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats
S. Cal et al., Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats, J BIOL CHEM, 276(21), 2001, pp. 17932-17940
We have identified and cloned a human fetal lung cDNA encoding a new protei
n of the ADAM-TS family (a disintegrin and metalloproteinase domain, with t
hrombospondin type-1 modules) that has been called ADAM-TS12, This protein
exhibits a domain organization similar to the remaining family members incl
uding a propeptide and metalloproteinase-like, disintegrin-like, and cystei
ne-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 int
racellular processing of ADAM-TS12 revealed that it is synthesized as a pre
cursor molecule that is first activated by cleavage of the prodomain in a f
urin-mediated process and subsequently processed into two fragments of diff
erent size: a 120-kDa N-terminal proteolytically active fragment containing
the metalloproteinase and disintegrin domains, and a 83-kDa C-terminal fra
gment containing most of the TS-1 repeats. Somatic cell hybrid and radiatio
n hybrid mapping experiments showed that the human ADAM-TS12 gene maps to 5
q35, a location that differs from all ADAM genes mapped to date. Northern b
lot analysis of RNAs from human adult and fetal tissues demonstrated that A
DAM-TS12 transcripts are only detected at significant levels in fetal lung
but not in any other analyzed tissues. In addition, ADAM-TS12 transcripts w
ere detected in gastric carcinomas and in tumor cell lines from diverse sou
rces, being induced by transforming growth factor-beta in KMST human fibrob
lasts, These data suggest that ADAM-TS12 may play roles in pulmonary cells
during fetal development or in tumor processes through its proteolytic acti
vity or as a molecule potentially involved in regulation of cell adhesion.