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Marfan syndrome-related mutations lead to abnormal trafficking of TGF-β family receptors

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TitleInfo
Title
Marfan syndrome-related mutations lead to abnormal trafficking of TGF-β family receptors
Name (type = personal)
NamePart (type = family)
Lin
NamePart (type = given)
Jing
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Jing Lin
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Padgett
NamePart (type = given)
Richard
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Richard Padgett
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Advisory Committee
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chair
Name (type = personal)
NamePart (type = family)
Driscoll
NamePart (type = given)
Monica
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Monica Driscoll
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Advisory Committee
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RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Singson
NamePart (type = given)
Andrew
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Andrew Singson
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Walworth
NamePart (type = given)
Nancy
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Nancy Walworth
Affiliation
Advisory Committee
Role
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outside member
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Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
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NamePart
School of Graduate Studies
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school
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Text
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theses
OriginInfo
DateCreated (encoding = w3cdtf); (keyDate = yes); (qualifier = exact)
2019
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2019-05
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
The 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.
Subject (authority = local)
Topic
TGF-β
Subject (authority = RUETD)
Topic
Cell and Developmental Biology
Subject (authority = LCSH)
Topic
Marfan syndrome -- Genetic aspects
Subject (authority = LCSH)
Topic
Transforming growth factors-beta
RelatedItem (type = host)
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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ETD_9663
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application/pdf
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text/xml
Extent
1 online resource (xviii, 126 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-sffa-ew68
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Lin
GivenName
Jing
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-04-02 16:34:14
AssociatedEntity
Name
Jing Lin
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-11-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after November 30th, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2019-04-03T16:28:14
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2019-04-03T16:28:14
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