{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:07:58Z","timestamp":1790770078717,"version":"4.1.0"},"reference-count":89,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010438","name":"Francis Crick Institute","doi-asserted-by":"publisher","award":["FC10095"],"award-info":[{"award-number":["FC10095"]}],"id":[{"id":"10.13039\/100010438","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Shprintzen\u2013Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys\u2013Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-\u03b2 signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-\u03b2 signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-\u03b2 responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-\u03b2-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.<\/jats:p>","DOI":"10.7554\/elife.63545","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T08:12:19Z","timestamp":1610093539000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.63545","source":"Crossref","is-referenced-by-count":36,"title":["Mutations in SKI in Shprintzen\u2013Goldberg syndrome lead to attenuated TGF-\u03b2 responses through SKI stabilization"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-8520","authenticated-orcid":true,"given":"Ilaria","family":"Gori","sequence":"first","affiliation":[{"name":"Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5547-337X","authenticated-orcid":true,"given":"Roger","family":"George","sequence":"additional","affiliation":[{"name":"Structural Biology Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-3509","authenticated-orcid":true,"given":"Andrew G","family":"Purkiss","sequence":"additional","affiliation":[{"name":"Structural Biology Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9781-6879","authenticated-orcid":true,"given":"Stephanie","family":"Strohbuecker","sequence":"additional","affiliation":[{"name":"Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A","family":"Randall","sequence":"additional","affiliation":[{"name":"Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roksana","family":"Ogrodowicz","sequence":"additional","affiliation":[{"name":"Structural Biology Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-6448","authenticated-orcid":true,"given":"Virginie","family":"Carmignac","sequence":"additional","affiliation":[{"name":"INSERM - Universit\u00e9 de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Faivre","sequence":"additional","affiliation":[{"name":"INSERM - Universit\u00e9 de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8660-2528","authenticated-orcid":true,"given":"Dhira","family":"Joshi","sequence":"additional","affiliation":[{"name":"Peptide Chemistry Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9767-8683","authenticated-orcid":true,"given":"Svend","family":"Kj\u00e6r","sequence":"additional","affiliation":[{"name":"Structural Biology Facility, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8632-0480","authenticated-orcid":true,"given":"Caroline S","family":"Hill","sequence":"additional","affiliation":[{"name":"Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards automated crystallographic structure refinement with phenix.refine","volume":"68","author":"Afonine","year":"2012","journal-title":"Acta Crystallographica Section D Biological Crystallography"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1177\/0192623311416259","article-title":"Induction of heart valve lesions by small-molecule ALK5 inhibitors","volume":"39","author":"Anderton","year":"2011","journal-title":"Toxicologic Pathology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"2102","DOI":"10.1161\/ATVBAHA.117.309401","article-title":"TGF-\u03b2 (Transforming growth Factor-\u03b2) Signaling protects the thoracic and abdominal aorta from angiotensin II-Induced pathology by distinct mechanisms","volume":"37","author":"Angelov","year":"2017","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s00441-011-1180-z","article-title":"c-Ski in health and disease","volume":"347","author":"Bonnon","year":"2012","journal-title":"Cell and Tissue Research"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1158\/0008-5472.CAN-12-1916","article-title":"Arkadia regulates tumor metastasis by modulation of the TGF-\u03b2 pathway","volume":"73","author":"Briones-Orta","year":"2013","journal-title":"Cancer Research"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.ejmg.2015.10.010","article-title":"TGF-\u03b2 signalopathies as a paradigm for translational medicine","volume":"58","author":"Cannaerts","year":"2015","journal-title":"European Journal of Medical Genetics"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3109\/10799893.2012.664553","article-title":"TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating","volume":"32","author":"Cardoso","year":"2012","journal-title":"Journal of Receptors and Signal Transduction"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/j.ajhg.2012.10.002","article-title":"In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome","volume":"91","author":"Carmignac","year":"2012","journal-title":"The American Journal of Human Genetics"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/ng770","article-title":"Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in ski-\/- mice","volume":"30","author":"Colmenares","year":"2002","journal-title":"Nature Genetics"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/cge.12436","article-title":"Cardiovascular manifestations in marfan syndrome and related diseases; multiple genes causing similar phenotypes","volume":"87","author":"Cook","year":"2015","journal-title":"Clinical Genetics"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1161\/ATVBAHA.114.305150","article-title":"Dimorphic effects of transforming growth factor-\u03b2 signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for marfan syndrome","volume":"35","author":"Cook","year":"2015","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1042\/BJ20080014","article-title":"An N-terminally truncated Smad2 protein can partially compensate for loss of full-length Smad2","volume":"417","author":"Das","year":"2009","journal-title":"Biochemical Journal"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1042\/bj20031886","article-title":"Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells","volume":"379","author":"De Bosscher","year":"2004","journal-title":"Biochemical Journal"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/cr.2008.324","article-title":"Ski and SnoN, potent negative regulators of TGF-\u03b2 signaling","volume":"19","author":"Deheuninck","year":"2009","journal-title":"Cell Research"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1093\/emboj\/17.11.3091","article-title":"Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene","volume":"17","author":"Dennler","year":"1998","journal-title":"The EMBO Journal"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/352337a0","article-title":"Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene","volume":"352","author":"Dietz","year":"1991","journal-title":"Nature"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nature21035","article-title":"Force interacts with macromolecular structure in activation of TGF-\u03b2","volume":"542","author":"Dong","year":"2017","journal-title":"Nature"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1038\/ng.2421","article-title":"Mutations in the TGF-\u03b2 repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm","volume":"44","author":"Doyle","year":"2012","journal-title":"Nature Genetics"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallographica. Section D, Biological Crystallography"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1038\/nmeth983","article-title":"Protein complex expression by using multigene baculoviral vectors","volume":"3","author":"Fitzgerald","year":"2006","journal-title":"Nature Methods"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1172\/JCI69666","article-title":"Angiotensin II-dependent TGF-\u03b2 signaling contributes to Loeys-Dietz syndrome vascular pathogenesis","volume":"124","author":"Gallo","year":"2014","journal-title":"Journal of Clinical Investigation"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1001\/jama.1989.03430040095032","article-title":"Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum","volume":"262","author":"Glesby","year":"1989","journal-title":"Jama"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1002\/(SICI)1096-8628(19980319)76:3<202::AID-AJMG2>3.0.CO;2-S","article-title":"Shprintzen-Goldberg syndrome: a clinical analysis","volume":"76","author":"Greally","year":"1998","journal-title":"American Journal of Medical Genetics"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"2904","DOI":"10.1128\/MCB.00231-12","article-title":"Transforming growth factor \u03b2 inhibits bone morphogenetic protein-induced transcription through novel phosphorylated Smad1\/5-Smad3 complexes","volume":"32","author":"Gr\u00f6nroos","year":"2012","journal-title":"Molecular and Cellular Biology"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1126\/science.1124287","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1126\/science.1192149","article-title":"Noncanonical tgf\u03b2 signaling contributes to aortic aneurysm progression in marfan syndrome mice","volume":"332","author":"Holm","year":"2011","journal-title":"Science"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.1242\/jcs.074773","article-title":"Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and smad signaling activity","volume":"123","author":"Horbelt","year":"2010","journal-title":"Journal of Cell Science"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1124\/mol.62.1.65","article-title":"SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7","volume":"62","author":"Inman","year":"2002","journal-title":"Molecular Pharmacology"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1016\/j.compbiolchem.2019.107159","article-title":"Computational investigation of a ternary model of SnoN-SMAD3-SMAD4 complex","volume":"83","author":"Ji","year":"2019","journal-title":"Computational Biology and Chemistry"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/ng0303-331","article-title":"Fibrillin controls TGF-\u03b2\u00a0activation","volume":"33","author":"Kaartinen","year":"2003","journal-title":"Nature Genetics"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallographica. Section D, Biological Crystallography"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1074\/jbc.M111023200","article-title":"Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter","volume":"277","author":"Korchynskyi","year":"2002","journal-title":"Journal of Biological Chemistry"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1158\/0008-5472.CAN-07-6793","article-title":"Transforming growth factor-beta suppresses the ability of ski to inhibit tumor metastasis by inducing its degradation","volume":"68","author":"Le Scolan","year":"2008","journal-title":"Cancer Research"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"6068","DOI":"10.1128\/MCB.00664-07","article-title":"Arkadia activates Smad3\/Smad4-dependent transcription by triggering signal-induced SnoN degradation","volume":"27","author":"Levy","year":"2007","journal-title":"Molecular and Cellular Biology"},{"key":"bib37","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","article-title":"Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in phenix","volume":"75","author":"Liebschner","year":"2019","journal-title":"Acta Crystallographica Section D Structural Biology"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1038\/ng.2349","article-title":"Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm","volume":"44","author":"Lindsay","year":"2012","journal-title":"Nature Genetics"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/ng1511","article-title":"A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2","volume":"37","author":"Loeys","year":"2005","journal-title":"Nature Genetics"},{"key":"bib41","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1101\/gad.13.17.2196","article-title":"The Ski oncoprotein interacts with the Smad proteins to repress TGF\u03b2 signaling","volume":"13","author":"Luo","year":"1999","journal-title":"Genes & Development"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.gde.2003.11.003","article-title":"Ski and SnoN: negative regulators of TGF-\u03b2 signaling","volume":"14","author":"Luo","year":"2004","journal-title":"Current Opinion in Genetics & Development"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1172\/JCI123547","article-title":"Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome","volume":"129","author":"MacFarlane","year":"2019","journal-title":"Journal of Clinical Investigation"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet.journal"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrm3434","article-title":"TGF\u03b2 signalling in context","volume":"13","author":"Massagu\u00e9","year":"2012","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"Journal of Applied Crystallography"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1016\/j.celrep.2018.10.056","article-title":"The dynamics of TGF-\u03b2 signaling are dictated by receptor trafficking via the ESCRT machinery","volume":"25","author":"Miller","year":"2018","journal-title":"Cell Reports"},{"key":"bib49","first-page":"1","volume-title":"Encyclopedia of Cell Biology","author":"Miller","year":"2016"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1093\/toxsci\/kfaa024","article-title":"A potent Pan-TGF\u03b2 neutralizing monoclonal antibody elicits cardiovascular toxicity in mice and cynomolgus monkeys","volume":"175","author":"Mitra","year":"2020","journal-title":"Toxicological Sciences"},{"key":"bib51","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aao7227","article-title":"Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors","volume":"11","author":"Miyazono","year":"2018","journal-title":"Science Signaling"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1107\/S0907444911001314","article-title":"REFMAC5 for the refinement of macromolecular crystal structures","volume":"67","author":"Murshudov","year":"2011","journal-title":"Acta Crystallographica Section D Biological Crystallography"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"20492","DOI":"10.1074\/jbc.M701294200","article-title":"Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling","volume":"282","author":"Nagano","year":"2007","journal-title":"Journal of Biological Chemistry"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/ng1116","article-title":"Dysregulation of TGF-\u03b2 activation contributes to pathogenesis in Marfan syndrome","volume":"33","author":"Neptune","year":"2003","journal-title":"Nature Genetics"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"4113","DOI":"10.1242\/jcs.01289","article-title":"Analysis of smad nucleocytoplasmic shuttling in living cells","volume":"117","author":"Nicol\u00e1s","year":"2004","journal-title":"Journal of Cell Science"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1101\/gad.13.4.412","article-title":"Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor","volume":"13","author":"Nomura","year":"1999","journal-title":"Genes & Development"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"19945","DOI":"10.1074\/jbc.M102382200","article-title":"Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts","volume":"276","author":"Piek","year":"2001","journal-title":"Journal of Biological Chemistry"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"9041","DOI":"10.1128\/MCB.20.23.9041-9054.2000","article-title":"Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus","volume":"20","author":"Pierreux","year":"2000","journal-title":"Molecular and Cellular Biology"},{"key":"bib59","article-title":"R: A language and environment for statistical computing","author":"R Development Core Team","year":"2009","unstructured":"R Development Core Team. 2009. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. http:\/\/www.r-project.org."},{"key":"bib60","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.31756","article-title":"TGF-\u03b2 uses a novel mode of receptor activation to phosphorylate SMAD1\/5 and induce epithelial-to-mesenchymal transition","volume":"7","author":"Ramachandran","year":"2018","journal-title":"eLife"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1152\/physiolgenomics.00092.2004","article-title":"Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology","volume":"19","author":"Ramirez","year":"2004","journal-title":"Physiological Genomics"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nature Protocols"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1093\/emboj\/21.1.145","article-title":"Different Smad2 partners bind a common hydrophobic pocket in Smad2 via a defined proline-rich motif","volume":"21","author":"Randall","year":"2002","journal-title":"The EMBO Journal"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1128\/MCB.24.3.1106-1121.2004","article-title":"Recognition of phosphorylated-Smad2-containing complexes by a novel smad interaction motif","volume":"24","author":"Randall","year":"2004","journal-title":"Molecular and Cellular Biology"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.matbio.2017.11.014","article-title":"LTBPs in biology and medicine: ltbp diseases","volume":"71-72","author":"Rifkin","year":"2018","journal-title":"Matrix Biology"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.matbio.2015.05.005","article-title":"Latent TGF-\u03b2-binding proteins","volume":"47","author":"Robertson","year":"2015","journal-title":"Matrix Biology"},{"key":"bib67","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021907","article-title":"Regulation of the bioavailability of TGF-\u03b2 and TGF-\u03b2-Related proteins","volume":"8","author":"Robertson","year":"2016","journal-title":"Cold Spring Harbor Perspectives in Biology"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/ejhg.2014.61","article-title":"The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome","volume":"23","author":"Schepers","year":"2015","journal-title":"European Journal of Human Genetics"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1002\/humu.23407","article-title":"A mutation update on the LDS-associated genes TGFB2\/3 and SMAD2\/3","volume":"39","author":"Schepers","year":"2018","journal-title":"Human Mutation"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/40431","article-title":"A structural basis for mutational inactivation of the tumour suppressor Smad4","volume":"388","author":"Shi","year":"1997","journal-title":"Nature"},{"key":"bib71","first-page":"65","article-title":"A recurrent pattern syndrome of craniosynostosis associated with arachnodactyly and abdominal hernias","volume":"2","author":"Shprintzen","year":"1982","journal-title":"Journal of Craniofacial Genetics and Developmental Biology"},{"key":"bib72","doi-asserted-by":"publisher","DOI":"10.4172\/2161-0495.196","article-title":"Nonclinical safety evaluation of a transforming growth factor \u03b2 receptor IKinase inhibitor in Fischer 344 rats and beagle dogs","volume":"4","author":"Stauber","year":"2014","journal-title":"Journal of Clinical Toxicology"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1126\/science.286.5440.771","article-title":"Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein","volume":"286","author":"Stroschein","year":"1999","journal-title":"Science"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"12442","DOI":"10.1073\/pnas.96.22.12442","article-title":"SnoN and ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling","volume":"96","author":"Sun","year":"1999","journal-title":"PNAS"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"4485","DOI":"10.1074\/jbc.274.8.4485","article-title":"Viral ski inhibits retinoblastoma protein (Rb)-mediated transcriptional repression in a dominant negative fashion","volume":"274","author":"Tokitou","year":"1999","journal-title":"Journal of Biological Chemistry"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"32489","DOI":"10.1074\/jbc.C300276200","article-title":"Direct interaction of ski with either Smad3 or Smad4 is necessary and sufficient for Ski-mediated repression of transforming growth factor-beta signaling","volume":"278","author":"Ueki","year":"2003","journal-title":"Journal of Biological Chemistry"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1136\/jmedgenet-2011-100382","article-title":"Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome","volume":"49","author":"van de Laar","year":"2012","journal-title":"Journal of Medical Genetics"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1002\/humu.22977","article-title":"Marfan syndrome and related disorders: 25 years of gene discovery","volume":"37","author":"Verstraeten","year":"2016","journal-title":"Human Mutation"},{"key":"bib79","doi-asserted-by":"publisher","DOI":"10.1038\/srep46370","article-title":"SnoN stabilizes the SMAD3\/SMAD4 protein complex","volume":"7","author":"Walld\u00e9n","year":"2017","journal-title":"Scientific Reports"},{"key":"bib80","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.004968","article-title":"Aortopathy in a mouse model of marfan syndrome is not mediated by altered transforming growth factor \u03b2 signaling","volume":"6","author":"Wei","year":"2017","journal-title":"Journal of the American Heart Association"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"S757","DOI":"10.1016\/j.athoracsur.2006.10.091","article-title":"Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease","volume":"83","author":"Williams","year":"2007","journal-title":"The Annals of Thoracic Surgery"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.str.2004.02.035","article-title":"Crystal structure of the dachshund homology domain of human SKI","volume":"12","author":"Wilson","year":"2004","journal-title":"Structure"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview of the CCP4 suite and current developments","volume":"67","author":"Winn","year":"2011","journal-title":"Acta Crystallographica. Section D, Biological Crystallography"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1107\/S0021889809045701","article-title":"xia2 : an expert system for macromolecular crystallography data reduction","volume":"43","author":"Winter","year":"2010","journal-title":"Journal of Applied Crystallography"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1128\/MCB.19.3.1821","article-title":"Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta","volume":"19","author":"Wong","year":"1999","journal-title":"Molecular and Cellular Biology"},{"key":"bib86","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1126\/science.287.5450.92","article-title":"Structural basis of Smad2 recognition by the smad anchor for receptor activation","volume":"287","author":"Wu","year":"2000","journal-title":"Science"},{"key":"bib87","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1016\/s1097-2765(01)00421-x","article-title":"Crystal structure of a phosphorylated Smad2. recognition of phosphoserine by the MH2 domain and insights on smad function in TGF-\u03b2 signaling","volume":"8","author":"Wu","year":"2001","journal-title":"Molecular Cell"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/s0092-8674(02)01006-1","article-title":"Structural mechanism of Smad4 recognition by the nuclear oncoprotein ski: insights on Ski-mediated repression of TGF-\u03b2 signaling","volume":"111","author":"Wu","year":"2002","journal-title":"Cell"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.gene.2013.07.024","article-title":"576 kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy","volume":"528","author":"Zhu","year":"2013","journal-title":"Gene"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/63545\/elife-63545-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/63545\/elife-63545-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/63545","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:05:04Z","timestamp":1697058304000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/63545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,8]]},"references-count":89,"alternative-id":["10.7554\/eLife.63545"],"URL":"https:\/\/doi.org\/10.7554\/elife.63545","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"accession","id":"EGAS00001004908","asserted-by":"subject"},{"id-type":"accession","id":"6ZVQ","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.63545.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.63545.sa1","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.07.330407","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,8]]},"article-number":"e63545"}}