{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAMTS9 is a secreted metalloprotease with multifaceted roles in extracellular matrix (ECM) remodeling that link developmental processes, metabolic traits, and tumor suppression. Genetic association studies have implicated variants in ADAMTS9 in type 2 diabetes risk and body fat distribution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural and biochemical analyses reveal that ADAMTS9 belongs to a subfamily characterized by numerous thrombospondin type‑1 repeats and a distinct C‑terminal domain; its zymogen is selectively processed by proprotein convertases (e.g., furin) to yield an active enzyme that localizes at the cell surface and within the ECM, where it cleaves substrates such as versican and aggrecan via its ancillary domains."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n During embryogenesis and tissue remodeling, ADAMTS9 is widely expressed in numerous organs, and its activity is critical for proper morphogenesis. In the developing palate, for example, ADAMTS9 cooperates with its close homolog ADAMTS20 to process versican and regulate palatal shelf remodeling, ensuring timely elevation and fusion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, in the umbilical cord, ADAMTS9 secreted by mesenchymal cells mediates versican proteolysis that is essential for vascular elongation and the regulation of smooth muscle cell proliferation and orientation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Independent expression studies have demonstrated a broad developmental distribution of ADAMTS9, underscoring its general role in ECM organization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of neoplasia, ADAMTS9 functions as a tumor suppressor. Its expression is frequently downregulated in several human cancers—such as gastric, esophageal, and nasopharyngeal carcinomas—often through promoter hypermethylation, a modification that compromises its antiangiogenic activity and facilitates tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, a long noncoding RNA transcribed from the antisense strand of the ADAMTS9 locus (ADAMTS9‑AS2) has been shown to act as a tumor suppressor in glioma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and similar anti‑angiogenic functions have been documented in studies of esophageal and nasopharyngeal cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ADAMTS9 is an essential enzyme that modulates the ECM by proteolitically processing key substrates, thereby orchestrating tissue remodeling during development, contributing to metabolic risk profiles, and restraining tumor growth via antiangiogenic mechanisms. Its diverse functions underscore the therapeutic potential of targeting ADAMTS9‐mediated pathways in metabolic disorders and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eleftheria Zeggini, Laura J Scott, Richa Saxena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.120"}], "href": "https://doi.org/10.1038/ng.120"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18372903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18372903"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Iris M Heid, Anne U Jackson, Joshua C Randall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.685"}], "href": "https://doi.org/10.1038/ng.685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20935629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20935629"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Robert P T Somerville, Jean-Michel Longpre, Katherine A Jungers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M211009200"}], "href": "https://doi.org/10.1074/jbc.M211009200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12514189"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12514189"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hiroyuki Enomoto, Courtney M Nelson, Robert P T Somerville, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.050591"}], "href": "https://doi.org/10.1242/dev.050591"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21041365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21041365"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sumeda Nandadasa, Courtney M Nelson, Suneel S Apte "}, {"type": "b", "children": [{"type": "t", "text": "ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2015.05.005"}], "href": "https://doi.org/10.1016/j.celrep.2015.05.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26027930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26027930"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Katherine A Jungers, Carine Le Goff, Robert P T Somerville, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adamts9 is widely expressed during mouse embryo development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene Expr Patterns (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.modgep.2005.03.004"}], "href": "https://doi.org/10.1016/j.modgep.2005.03.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15939373"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15939373"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "W Du, S Wang, Q Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.359"}], "href": "https://doi.org/10.1038/onc.2012.359"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22907434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22907434"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Bon-Hun Koo, David M Coe, Laura J Dixon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2010.090655"}], "href": "https://doi.org/10.2353/ajpath.2010.090655"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20093484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20093484"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jie Yao, Baosheng Zhou, Jian Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-014-1949-2"}], "href": "https://doi.org/10.1007/s13277-014-1949-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24833086"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24833086"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Paulisally Hau Yi Lo, Hong Lok Lung, Arthur Kwok Leung Cheung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-4510"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-4510"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20551050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20551050"}]}]}]}