Biosynthesis and Expression of a Disintegrin-like and Metalloproteinase Domain with Thrombospondin-1 Repeats-15

By Carolyn M. Dancevic, Fiona W. Fraser, A. Smith, N. Stupka, A. Ward, D. McCulloch. 2013

55 citations recorded by the source corpus.

Background: ADAMTS proteoglycanases show proteolytic activity toward versican and other proteoglycans. Results: ADAMTS15, which cleaves versican, is expressed during early cardiac development and during musculoskeletal development. Conclusion: With unique and overlapping biological properties, ADAMTS15 is likely to have cooperative roles with other members of the ADAMTS proteoglycanase clade. Significance: Versican cleavage has profound effects on developmental morphogenesis and regulates cancer cell behavior. 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 RAKR212↓ 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 441E↓A442. 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.

Subfields: Cancer Research, Cell Biology, Molecular Biology

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In Cancer Research

1. Hideaki Nagase
2. D. Edwards
3. Gillian Murphy
4. R. Khalil

In Molecular Biology

1. Hideaki Nagase
2. D. Edwards

Citations in the corpus

• The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “Antibodies against DPEAAE have shown that ADAMTS1, 4, 5, 9, 15 and 20 are versicanases in various contexts [68–70], including cardiac development [71, 72], limb morphogenesis [73], palate formation [74], skin pigmentation [75], and myogenesis [76, 77].”
• Metalloproteinase‐dependent and ‐independent processes contribute to inhibition of breast cancer cell migration, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs‐15 (2015, background): “We demonstrated that ADAMTS-15 is a functional hyalectanase, albeit with weak aggrecanase activity as compared to that of ADAMTS-5; likewise ADAMTS-15 has recently been shown to cleave versican, a chondroitin sulfate proteoglycan (CSPG).(38,39) Thus, given the link between ADAMTS1-mediated cleavage ”