{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:27:41Z","timestamp":1791296861929,"version":"4.1.0"},"reference-count":53,"publisher":"The Company of Biologists","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,12,15]]},"abstract":"<jats:p>Mutations in the gene encoding transforming growth factor-beta receptor type II (TGFBR2) have been described in patients with Loeys\u2013Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). Here, we present a comprehensive and quantitative analysis of TGFBR2 expression, turnover and TGF-\u03b2-induced Smad and ERK signaling activity for nine mutations identified in patients with LDS, MFS2 and TAAD. The mutations had different effects on protein stability, internalization and signaling. A dominant-negative effect was demonstrated for mutations associated with LDS and MFS2. No mutation showed evidence of an immediate cell-autonomous paradoxical activation of TGF-\u03b2 signaling. There were no cell biological differences between mutations described in patients with LDS and MFS2. By contrast, R460C, which has been found in familial TAAD but not in MFS2 or LDS, showed a less-severe dominant-negative effect and retained residual Smad phosphorylation and transcriptional activity. TAAD is characterized primarily by thoracic aortic aneurysms or dissections. By contrast, MFS2 is characterized by numerous skeletal abnormalities, and patients with LDS additionally can display craniofacial and other abnormalities. Therefore, our findings suggest that the balance between defects in Smad and ERK signaling might be an important determinant of phenotypic severity in disorders related to mutations in TGFBR2.<\/jats:p>","DOI":"10.1242\/jcs.074773","type":"journal-article","created":{"date-parts":[[2010,11,24]],"date-time":"2010-11-24T03:18:06Z","timestamp":1290568686000},"page":"4340-4350","source":"Crossref","is-referenced-by-count":66,"title":["Quantitative analysis of <i>TGFBR2<\/i> mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity"],"prefix":"10.1242","volume":"123","author":[{"given":"Daniel","family":"Horbelt","sequence":"first","affiliation":[{"name":"Institute for Chemistry-Biochemistry, Freie Universit\u00e4t Berlin, Berlin, 14195, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gao","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute for Medical Genetics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, 13353, Germany"},{"name":"Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter N.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Institute for Medical Genetics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, 13353, Germany"},{"name":"Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany"},{"name":"Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, 13353, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Knaus","sequence":"additional","affiliation":[{"name":"Institute for Chemistry-Biochemistry, Freie Universit\u00e4t Berlin, Berlin, 14195, Germany"},{"name":"Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, 13353, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042521180734600_R1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"2021042521180734600_R2","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1161\/CIRCULATIONAHA.109.887042","article-title":"Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders","volume":"120","author":"Attias","year":"2009","journal-title":"Circulation"},{"key":"2021042521180734600_R3","doi-asserted-by":"crossref","first-page":"36803","DOI":"10.1074\/jbc.M005912200","article-title":"Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration","volume":"275","author":"Bakin","year":"2000","journal-title":"J. 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