Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans
Open accessAbstract
Significance: Down-regulation of TGFβ signaling is a therapeutic strategy for several disease applications, particularly cancer and fibrosis. However, TGFβ blockade may have adverse effects because TGFβ signaling is necessary for formation and maintenance of normal blood vessels. Because side effects may vary between individuals due to innate differences in genetic makeup, it is important to find which interindividual genetic variants regulate responses to reduced TGFβ signaling and how these operate at the molecular level. Here we identified polymorphic variants of mouse a disintegrin and metalloprotease 17 that differentially regulate TGFβ signaling output and influence the severity of Tgfb1- dependent vascular pathology. This has relevance to risk assessment for clinical manifestations in TGFβ-driven diseases, as well as for prediction of desirable and undesirable responses to anti-TGFβ therapy.
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Basic and Therapeutic Aspects of Angiogenesis
Potente, M., Gerhardt, H., & Carmeliet, P. (2011) · Cell · doi:10.1016/j.cell.2011.08.039 · Cited by 2,771 · see citing works
Kulkarni, A. B., Huh, C. G., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., & Karlsson, S. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.2.770 · Cited by 1,967 · see citing works
Loeys, B., Chen, J., Neptune, E., Judge, D. P., Podowski, M., Holm, T. M., Meyers, J. L., Leitch, C. C., Katsanis, N., Sharifi, N., et al. (2005) · Nature Genetics · doi:10.1038/ng1511 · Cited by 1,786 · see citing works
Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor
Loeys, B., Schwarze, U., Holm, T. M., Callewaert, B. L., Thomas, G. H., Pannu, H., Backer, J. F. A. D., Oswald, G. L., Symoens, S., Manouvrier‐Hanu, S., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa055695 · Cited by 1,650 · see citing works
An Essential Role for Ectodomain Shedding in Mammalian Development
Peschon, J. J., Slack, J. L., Reddy, P., Stocking, K. L., Sunnarborg, S. W., Lee, D. C., Russell, W. E., Castner, B. J., Johnson, R. S., Fitzner, J. N., et al. (1998) · Science · doi:10.1126/science.282.5392.1281 · Cited by 1,606 · see citing works
Targeting the TGFβ signalling pathway in disease
Akhurst, R. J., & Hata, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3810 · Cited by 1,466 · see citing works
Self-citationJohnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-H., Stenzel, T. T., Speer, M. C., Pericak‐Vance, M. A., Diamond, A. G., et al. (1996) · Nature Genetics · doi:10.1038/ng0696-189 · Cited by 1,113 · see citing works
Defective haematopoiesis and vasculogenesis in transforming growth factor-β1 knock out mice
Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S., & Akhurst, R. J. (1995) · Development · doi:10.1242/dev.121.6.1845 · Cited by 1,029 · see citing works
Self-citationThe art and design of genetic screens: Drosophila melanogaster
St Johnston, D. (2002) · Nature Reviews Genetics · doi:10.1038/nrg751 · Cited by 644 · cited 1× · see citing works
“Indeed, classical forward genetic screens for suppressors of gene knockout phenotypes have been used extensively in lower organisms to identify novel components of specific signaling pathways (20).”
BackgroundADAM17: a molecular switch to control inflammation and tissue regeneration
Scheller, J., Chalaris, A., Garbers, C., & Rose‐John, S. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.05.005 · Cited by 526 · see citing works
Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment
Shovlin, C. L. (2010) · Blood Reviews · doi:10.1016/j.blre.2010.07.001 · Cited by 503 · see citing works
Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm
Lindsay, M. E., Schepers, D., Bolar, N. A., Doyle, J. J., Gallo, E. M., Fert‐Bober, J., Kempers, M. J. E., Fishman, E. K., Chen, Y., Myers, L. A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2349 · Cited by 482 · see citing works
Signaling by members of the TGF-β family in vascular morphogenesis and disease
Pardali, E., Goumans, M., & ten Dijke, P. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.06.006 · Cited by 402 · see citing works
Dupuis‐Girod, S., Ginon, I., Saurin, J., Marion, D., Guillot, E., Decullier, É., Roux, A. S., Carette, M., Gilbert‐Dussardier, B., Hatron, P., et al. (2012) · JAMA · doi:10.1001/jama.2012.250 · Cited by 378 · see citing works
Self-citationALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway
Larrivée, B., Prahst, C., Gordon, E., del Toro, R., Mathivet, T., Duarte, A., Simons, M., & Eichmann, A. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.02.005 · Cited by 359 · see citing works
Epistasis and Its Implications for Personal Genetics
Moore, J. H., & Williams, S. M. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.08.006 · Cited by 347 · see citing works
Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis
Shaked, Y., Bertolini, F., Man, S., Rogers, M. S., Cervi, D., Foutz, T. J., Rawn, K., Voskas, D., Dumont, D., Ben‐David, Y., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.023 · Cited by 329 · see citing works
Morel, L. M., Blenman, K., Croker, B. P., & Wakeland, E. K. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1787 · Cited by 317 · see citing works
Inflammatory Skin and Bowel Disease Linked toADAM17Deletion
Blaydon, D. C., Biancheri, P., Di, W., Plagnol, V., Cabral, R. M., Brooke, M. A., van Heel, D. A., Rüschendorf, F., Toynbee, M., Walne, A. J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1100721 · Cited by 307 · see citing works
Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors
Anderton, M. J., Mellor, H. R., Bell, A., Sadler, C., Pass, M., Powell, S., Steele, S. J., Roberts, R. R. A., & Heier, A. (2011) · Toxicologic Pathology · doi:10.1177/0192623311416259 · Cited by 284 · see citing works
Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm
Doyle, A. J., Doyle, J. J., Bessling, S. L., Maragh, S., Lindsay, M. E., Schepers, D., Gillis, E., Mortier, G. R., Homfray, T., Sauls, K., et al. (2012) · Nature Genetics · doi:10.1038/ng.2421 · Cited by 265 · see citing works
SMAD4 mutations found in unselected HHT patients
Gallione, C. J., Richards, J., Letteboer, T. G. W., et al. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2006.041517 · Cited by 259 · see citing works
Self-citationSobrino, T., Hurtado, O., Moro, M. Á., Rodríguez‐Yáñez, M., Castellanos, M., Brea, D., Moldes, O., Blanco, M., Arenillas, J. F., Leira, R., et al. (2007) · Stroke · doi:10.1161/strokeaha.107.484386 · Cited by 232 · see citing works
Level and Value of Circulating Endothelial Progenitor Cells in Patients After Acute Ischemic Stroke
Yip, H., Chang, L., Chang, W., Lu, C., Liou, C., Lan, M., Liu, J. S., Youssef, A. A., & Chang, H. (2007) · Stroke · doi:10.1161/strokeaha.107.489401 · Cited by 220 · see citing works
Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C‐shaped scaffold
Takeda, S., Igarashi, T., Mori, H., & Araki, S. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601131 · Cited by 202 · cited 1× · see citing works
“Ileu613Val variant is located within the cysteine-rich substrate recognition domain (43); thus, variation in Adam17 p.”
BackgroundGao, D., Nolan, D., McDonnell, K., Vahdat, L. T., Benezra, R., Altorki, N. K., & Mittal, V. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2009.05.001 · Cited by 178 · see citing works
Werner, N., Waßmann, S., Ahlers, P., Schiegl, T., Kosiol, S., Link, A., Walenta, K. L. H., & Nickenig, G. (2007) · Basic Research in Cardiology · doi:10.1007/s00395-007-0680-1 · Cited by 169 · see citing works
Mapping of a major genetic modifier of embryonic lethality in TGFβ1 knockout mice
Bonyadi, M., Rusholme, S. A. B., Cousins, F. M., Su, H. C., Biron, C. A., Farrall, M., & Akhurst, R. J. (1997) · Nature Genetics · doi:10.1038/ng0297-207 · Cited by 166 · see citing works
Self-citationTACE-Mediated Ectodomain Shedding of the Type I TGF-β Receptor Downregulates TGF-β Signaling
Liu, C., Xu, P., Lamouille, S., Xu, J., & Derynck, R. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.018 · Cited by 140 · see citing works
McAllister, K. A., Baldwin, M. A., Thukkani, A. K., et al. (1995) · Human Molecular Genetics · doi:10.1093/hmg/4.10.1983 · Cited by 112 · see citing works
Role of endothelial progenitor cells during ischemia-induced vasculogenesis and collateral formation
Tongers, J., Roncalli, J. G., & Losordo, D. W. (2010) · Microvascular Research · doi:10.1016/j.mvr.2010.01.012 · Cited by 106 · see citing works
Li, H., McMillen, W. T., Heap, C. R., McCann, D., Yan, L., Campbell, R. M., Mundla, S. R., King, C.-H. R., Dierks, E. A., Anderson, B. D., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701199p · Cited by 68 · see citing works
Benzinou, M., Clermont, F. F., Letteboer, T. G. W., Kim, J.-H., Espejel, S., Harradine, K. A., Arbelaez, J., Luu, M. T., Roy, R., Quigley, D. A., et al. (2012) · Nature Communications · doi:10.1038/ncomms1633 · Cited by 67 · see citing works
Self-citationAssociation testing with Mendel
Lange, K. L., Sinsheimer, J. S., & Sobel, E. M. (2005) · Genetic Epidemiology · doi:10.1002/gepi.20073 · Cited by 65 · see citing works
Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis.
Thabet, M. M., & Huizinga, T. W. J. (2006) · PubMed · Cited by 61 · see citing works
Samuelson, D. J., Hesselson, S., Aperavich, B. A., Zan, Y., Haag, J. D., Trentham‐Dietz, A., Hampton, J. M., Mau, B., Chen, K.-S., Baynes, C., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701687104 · Cited by 60 · see citing works
Kim, J.-H., Peacock, M. R., George, S. C., & Hughes, C. C. W. (2012) · Angiogenesis · doi:10.1007/s10456-012-9277-x · Cited by 60 · see citing works
Nagase, H., Mao, J., de Koning, J. P., Minami, T., & Balmain, A. (2001) · PubMed · Cited by 60 · see citing works
Wara, A. K., Foo, S., Croce, K., Sun, X., Icli, B., Tesmenitsky, Y., Esen, F., Lee, J.-S., Subramaniam, M., Spelsberg, T. C., et al. (2011) · Blood · doi:10.1182/blood-2011-06-363713 · Cited by 50 · see citing works
The waved with open eyelids (woe) Locus Is a Hypomorphic Mouse Mutation in Adam17
Hassemer, E. L., Gall, S. M. L., Liegel, R. P., McNally, M. T., Chang, B., Zeiss, C. J., Dubielzig, R. D., Horiuchi, K., Kimura, T., Okada, Y., et al. (2010) · Genetics · doi:10.1534/genetics.109.113167 · Cited by 47 · see citing works
Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping of Sles1 to Less Than 1 Mb
Subramanian, S., Yim, Y., Liu, K., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.2.1062 · Cited by 43 · see citing works
Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(-/-) mice.
Tang, Y., McKinnon, M., Leong, L., Rusholme, S., Wang, S., & Akhurst, R. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg164 · Cited by 39 · see citing works
Self-citationSamuelson, D. J., Aperavich, B. A., Haag, J. D., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1498 · Cited by 31 · see citing works
Tang, Y., Lee, K. S., Yang, H., Logan, D. W., Wang, S., McKinnon, M. L., Holt, L. J., Condie, A., Luu, M. T., & Akhurst, R. J. (2004) · Genomics · doi:10.1016/j.ygeno.2004.09.003 · Cited by 27 · see citing works
Self-citationKang, H. C., Quigley, D. A., Kim, I.-J., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.45 · Cited by 25 · see citing works
Parietti, E., Pallandre, J., Deschaseaux, F., et al. (2011) · European Journal of Cardio-Thoracic Surgery · doi:10.1016/j.ejcts.2011.02.065 · Cited by 19 · see citing works
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Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
Self-citationDodagatta-Marri, E., Meyer, D. S., Reeves, M. Q., Paniagua, R., To, M. D., Binnewies, M., Broz, M. L., Mori, H., Wu, D., Adoumie, M., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0493-9 · Cited by 177 · see citing works
Self-citationGenetic factors in cerebral small vessel disease and their impact on stroke and dementia
Haffner, C., Malik, R., & Dichgans, M. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.71 · Cited by 109 · see citing works
Matters of context guide future research in TGFβ superfamily signaling
Akhurst, R. J., & Padgett, R. W. (2015) · Science Signaling · doi:10.1126/scisignal.aad0416 · Cited by 52 · see citing works
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- Authors
- Kawasaki, K., Freimuth, J., Meyer, D. S., Lee, M. M., Tochimoto-Okamoto, A., Benzinou, M., Clermont, F. F., Wu, G., Roy, R., Letteboer, T. G. W., Ploos van Amstel, J. K., Giraud, S., Dupuis-Girod, S., Lesca, G., Westermann, C. J. J., Coffey, R. J., & Akhurst, R. J.
- Affiliations
- University of California, San Francisco (US)
- Department of Medical Genetics, University Medical Centre, KC04.084.2, Utrecht, The Netherlands;
- Hospices Civils de Lyon (FR)
- French Hereditary Hemorrhagic Telangiectasia Reference Center, Department of Medical Genetics, Lyon University Hospital, 69622 Villeurbanne, France;
- St. Antonius Ziekenhuis (NL)
- Vanderbilt University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-08
- Volume
- 111
- Issue
- 21
- Pages
- 7723-7728
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4040598
- OpenAlex
- W2155002295
- Cited by
- 47
- References
- 46
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 6 · 2014: 1 · 2013: 1
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Heart Association
- Belgian American Educational Foundation
- Uehara Memorial Foundation
- National Institutes of Health (5r01hl078564-05)
- National Heart, Lung, and Blood Institute (HL078564, R01-HL078564)
- National Cancer Institute (R01CA116019, CA116019, R01CA046413)
- National Institute of General Medical Sciences (R01GM060514, GM60514)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Genetics › Vascular Anomalies and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ADAM17, TGF-beta signaling, Smad2, genetic polymorphism, endothelial progenitor cells, angiogenesis, hereditary hemorrhagic telangiectasia, CD105, ALK1, pulmonary arteriovenous malformation, vascular disease, modifier locus
- MeSH terms
- ADAM17 Protein, Animals, Blood Vessels, Gene Expression Regulation, Humans, Immunohistochemistry, Luciferases, Mice, Inbred C57BL, Genetic Variation, Signal Transduction, Transforming Growth Factor beta, NIH 3T3 Cells, Mice, ADAM Proteins, Smad2 Protein, Transforming Growth Factor beta1
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