Biosynthesis and expression of a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats-15: a novel versican-cleaving proteoglycanase.
The proteoglycanase clade of the ADAMTS superfamily shows preferred proteolytic activity toward the hyalectan/lectican proteoglycans as follows: aggrecan, brevican, neurocan, and versican. ADAMTS15, a member of this clade, was recently identified as a putative tumor suppressor gene in colorectal and breast cancer. However, its biosynthesis, substrate specificity, and tissue expression are poorly described. Therefore, we undertook a detailed study of this proteinase and its expression. We report propeptide processing of the ADAMTS15 zymogen by furin activity, identifying RAKR(212)↓ as a major furin cleavage site within the prodomain. ADAMTS15 was localized on the cell surface, activated extracellularly, and required propeptide processing before cleaving V1 versican at position (441)E↓A(442). In the mouse embryo, Adamts15 was expressed in the developing heart at E10.5 and E11.5 days post-coitum and in the musculoskeletal system from E13.5 to E15.5 days post-coitum, where it was co-localized with hyaluronan. Adamts15 was also highly expressed in several structures within the adult mouse colon. Our findings show overlapping sites of Adamts15 expression with other members of ADAMTS proteoglycanases during embryonic development, suggesting possible cooperative roles during embryogenesis, consistent with other ADAMTS proteoglycanase combinatorial knock-out mouse models. Collectively, these data suggest a role for ADAMTS15 in a wide range of biological processes that are potentially mediated through the processing of versican.
['Dancevic|Carolyn M|CM|', 'Fraser|Fiona W|FW|', 'Smith|Adam D|AD|', 'Stupka|Nicole|N|', 'Ward|Alister C|AC|', 'McCulloch|Daniel R|DR|']
D051722:ADAM Proteins D000818:Animals D019556:COS Cells D002522:Chlorocebus aethiops D004622:Embryo, Mammalian D047108:Embryonic Development D004792:Enzyme Precursors D045683:Furin D018507:Gene Expression Regulation, Developmental D015971:Gene Expression Regulation, Enzymologic D057809:HEK293 Cells D006801:Humans D018345:Mice, Knockout D009928:Organ Specificity D011817:Rabbits D053675:Versicans
Proteoglycan Embryo Development Extracellular Matrix Extracellular Matrix Proteins Metalloprotease Skeletal Muscle