Identification, characterization, and intracellular processing of ADAM-TS12, a novel human disintegrin with a complex structural organization involving multiple thrombospondin-1 repeats.
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.
Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006 Oviedo and Servicio de Anatomia Patológica, Hospital Clinico-IDIBAPS, 08036 Barcelona, Spain.
S
S
Cal
J M
JM
Arguelles
P L
PL
Fernandez
C
C
López-Otín
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D019483:Disintegrins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019699:Thrombospondins / Q000235:genetics
D019483:Disintegrins; D011498:Protein Precursors; D019699:Thrombospondins; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human; D008666:Metalloendopeptidases