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Marfan syndrome-related mutations lead to abnormal trafficking of TGF-β family receptors
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Lin, Jing. Marfan syndrome-related mutations lead to abnormal trafficking of TGF-β family receptors. Retrieved from https://doi.org/doi:10.7282/t3-sffa-ew68

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TitleMarfan syndrome-related mutations lead to abnormal trafficking of TGF-β family receptors
NameLin, Jing (author); Padgett, Richard (chair); Driscoll, Monica (internal member); Singson, Andrew (internal member); Walworth, Nancy (outside member); Rutgers University; School of Graduate Studies
Date Created2019
Other Date2019-05 (degree)
SubjectTGF-β, Cell and Developmental Biology, Marfan syndrome -- Genetic aspects, Transforming growth factors-beta
Extent1 online resource (xviii, 126 pages) : illustrations
DescriptionThe transforming growth factor-β (TGF-β) family includes a wide range of secreted, soluble proteins that are structurally similar growth factors; they play pivotal roles in various developmental processes. TGF-β ligand binding to TGF-β type I and type II receptors, which are located on the cell membrane, trigger the whole signaling cascade. The activated type I and type II receptors bind with the ligand to form a receptor complex, which further activates downstream signal transducer SMADs by phosphorylation. Eventually the activated pSMADs translocate to the nucleus to regulate specific gene expression.
The mis-regulation of TGF-β signaling is associated with several genetic diseases, including Marfan syndrome (MFS). MFS is an autosomal dominant genetic disorder of connective tissue that affects the ocular, skeletal, cardiovascular and pulmonary systems, often leads to death in early adult life. The cause of MFS can be directly attributed to germ line mutations in fibrillins. As shown by several recent studies, fibrillin mutations lead to excessive levels of bioactive TGF-β in the tissue microenvironment.
Other components in the TGF-β pathway can also be disrupted to result in related disorders; usually these show milder manifestations of the phenotypes seen in MFS. Most of these MFS-like disorders can be attributed to heterozygous missense germ line mutations in either TGF-β type II or type I receptor genes, and most of these mutations fall into the C-terminal domain in TGF-β receptors. Sequences in the C-terminal domain of the receptors are important for proper trafficking. The C-terminus tail in type II receptor regulates its endocytosis, via what is defined as the LTA motif. Many MFS-like associated amino acids reside in LTA motif, which lead to the hypothesis that these disease mutations may disrupt the normal trafficking route of TGF-β receptors.
I tested this hypothesis by engineering MFS-like mutations into the nematode type II receptor and testing resulting its activity and trafficking. Based on my observations using the model organism C. elegans, I found that some of these MFS-like phenotypes cause mis-trafficking of TGF-β receptors.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-sffa-ew68
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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