{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAM19 is a membrane‐anchored metalloprotease that plays multifaceted roles in both normal development and disease pathogenesis. In the developing heart, for example, Meltrin β/ADAM19 is essential for proper endocardial cushion formation by finely regulating the proteolytic processing of ErbB ligands such as type I neuregulin, thereby influencing epithelial‐to‐mesenchymal transformation and cardiac morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In vitro studies of soluble ADAM19 have demonstrated its constitutive catalytic activity, with the enzyme capable of cleaving substrates including myelin basic protein and peptides corresponding to the cleavage sites of cytokines such as TNF‐α–related activation‐induced cytokine and kit ligand–1, even acting as a negative regulator of shedding in certain contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In ovarian epithelial cells, intact TGF‐β/SMAD signaling is required for ADAM19 expression, and epigenetic suppression of ADAM19 has been observed in ovarian cancers with disrupted TGF‐β responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, oncogenic functions for ADAM19 have been described in non–small‐cell lung and colon cancers, where dysregulation by microRNAs (miR‐153 and miR‐30c, respectively) leads to enhanced cellular migration and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " ADAM19 is also upregulated in renal fibrosis through TGF‐β/Smad signaling and miR‐29 family down‐regulation, implicating it in extracellular matrix remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " At the molecular level, ADAM19 is processed into its active form by furin‐mediated cleavage in the secretory pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and it exhibits constitutive α‐secretase activity on the amyloid precursor protein."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Furthermore, ADAM19 can contribute to cytokine processing – for example, participating in TNF‐α shedding in a cell‐type–dependent manner"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "– and may influence neuregulin 1 cleavage, which has further implications in neuropsychiatric disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Finally, several genetic association studies have linked ADAM19 to pulmonary function, bone mineral density, and airflow obstruction, and even suggest a role in Alzheimer’s disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": " Collectively, these findings underscore a complex and context‐dependent role for ADAM19 in mediating the ectodomain shedding of key regulatory proteins – a function that is central not only to normal organogenesis but also to the pathogenesis of diverse cardiovascular, pulmonary, metabolic, fibrotic, neuropsychiatric, and malignant diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kazuto Kurohara, Kouji Komatsu, Tomohiro Kurisaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Essential roles of Meltrin beta (ADAM19) in heart development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2003.10.021"}], "href": "https://doi.org/10.1016/j.ydbio.2003.10.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14975714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14975714"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Valérie Chesneau, J David Becherer, Yufang Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Catalytic properties of ADAM19."}]}, {"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.M302781200"}], "href": "https://doi.org/10.1074/jbc.M302781200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12682046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12682046"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nobuko Kawaguchi, Keisuke Horiuchi, J David Becherer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.03403"}], "href": "https://doi.org/10.1242/jcs.03403"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17344430"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17344430"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jian-Liang Chou, Her-Young Su, Lin-Yu Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoter hypermethylation of FBXO32, a novel TGF-beta/SMAD4 target gene and tumor suppressor, is associated with poor prognosis in human ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/labinvest.2009.138"}], "href": "https://doi.org/10.1038/labinvest.2009.138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20065949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20065949"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Michael Wy Chan, Yi-Wen Huang, Corinna Hartman-Frey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant transforming growth factor beta1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neoplasia (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1593/neo.08540"}], "href": "https://doi.org/10.1593/neo.08540"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18714391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18714391"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nianxi Shan, Liangfang Shen, Jun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2014.11.093"}], "href": "https://doi.org/10.1016/j.bbrc.2014.11.093"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25475731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25475731"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Qian Zhang, Lei Yu, Dandan Qin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of microRNA-30c targeting ADAM19 in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0120698"}], "href": "https://doi.org/10.1371/journal.pone.0120698"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25799050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25799050"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Vasudev Ramdas, Martin McBride, Laura Denby, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Canonical transforming growth factor-β signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2013.08.027"}], "href": "https://doi.org/10.1016/j.ajpath.2013.08.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24103556"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24103556"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tiebang Kang, Yun-Ge Zhao, Duanqing Pei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular activation of human adamalysin 19/disintegrin and metalloproteinase 19 by furin occurs via one of the two consecutive recognition sites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M203532200"}], "href": "https://doi.org/10.1074/jbc.M203532200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12006600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12006600"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Chiaki Tanabe, Nika Hotoda, Noboru Sasagawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.10.181"}], "href": "https://doi.org/10.1016/j.bbrc.2006.10.181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17112471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17112471"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Atsuhiko Hikita, Nobuho Tanaka, Shoji Yamane, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/o09-015"}], "href": "https://doi.org/10.1139/o09-015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19767822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19767822"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Ketan Marballi, Dianne Cruz, Peter Thompson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential neuregulin 1 cleavage in the prefrontal cortex and hippocampus in schizophrenia and bipolar disorder: preliminary findings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0036431"}], "href": "https://doi.org/10.1371/journal.pone.0036431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22590542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22590542"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Dana B Hancock, Mark Eijgelsheim, Jemma B Wilk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function."}]}, {"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.500"}], "href": "https://doi.org/10.1038/ng.500"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20010835"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20010835"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Unnur Styrkarsdottir, Bjarni V Halldorsson, Solveig Gretarsdottir, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New sequence variants associated with bone mineral density."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.284"}], "href": "https://doi.org/10.1038/ng.284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19079262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19079262"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jemma B Wilk, Nick R G Shrine, Laura R Loehr, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Crit Care Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1164/rccm.201202-0366OC"}], "href": "https://doi.org/10.1164/rccm.201202-0366OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22837378"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22837378"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xingbin Wang, Oscar L Lopez, Robert A Sweet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic determinants of disease progression in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-140729"}], "href": "https://doi.org/10.3233/JAD-140729"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25114068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25114068"}]}]}]}