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.
From the School of Medicine, Faculty of Health, and Molecular and Medical Research SRC, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria 3216, Australia.
Carolyn M
CM
Dancevic
Fiona W
FW
Fraser
Adam D
AD
Smith
Nicole
N
Stupka
Alister C
AC
Ward
Daniel R
DR
McCulloch
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology*; D004792:Enzyme Precursors / Q000096:biosynthesis* / Q000235:genetics; D045683:Furin / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D018345:Mice, Knockout; D009928:Organ Specificity / Q000502:physiology; D011817:Rabbits; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
D004792:Enzyme Precursors; C508323:Vcan protein, mouse; D053675:Versicans; D045683:Furin; D051722:ADAM Proteins
Development; Embryo; Extracellular Matrix; Extracellular Matrix Proteins; Metalloprotease; Proteoglycan; Skeletal Muscle