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The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation

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TitleInfo
Title
The functional interplay between TPRM7 channel-kinase autophosphorylation and its cellular regulation
Name (type = personal)
NamePart (type = family)
Cai
NamePart (type = given)
Na
NamePart (type = date)
1988-
DisplayForm
Na Cai
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Runnels
NamePart (type = given)
Loren W
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Loren W Runnels
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Advisory Committee
Role
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chair
Name (type = personal)
NamePart (type = family)
Walworth
NamePart (type = given)
Nancy C
DisplayForm
Nancy C Walworth
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Madura
NamePart (type = given)
Kiran
DisplayForm
Kiran Madura
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Jin
NamePart (type = given)
Shengkan (Victor)
DisplayForm
Shengkan (Victor) Jin
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Stock
NamePart (type = given)
Ann M
DisplayForm
Ann M Stock
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-05
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2018
Place
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xx
Language
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eng
Abstract (type = abstract)
As a member of the transient receptor potential ion channel subfamily, TRPM7 is a remarkable ion channel in possession of its own functional kinase domain. TRPM7 is ubiquitously expressed and permeable to divalent cations, allowing Mg2+, Ca2+, and trace metals ions such as Zn2+ to constitute the channel’s characteristic small inward current. The channel’s functional kinase domain is located at the protein’s cytosolic COOH terminus, placing TRPM7 also into a family of serine/threonine-phosphorylating alpha-kinases. It is not intuitively clear why a channel is covalently linked to a kinase, especially as it has been found that the kinase activity of TRPM7 is not required for channel gating. Previous studies have shown that TRPM7 is autophosphorylated, and yet the functional outcome of this autophosphorylation remain unknown. Motivated to understand the impact of phosphorylation on the function and regulation of this channel-kinase, I performed a comprehensive phosphoproteomic analysis of TRPM7 by mass spectrometry to identify the major in vivo phosphorylation sites on TRPM7. The results of the mass spectrometry study uncovered potential mechanisms by which the catalytic activity of TRPM7 kinase is regulated through autophosphorylation. My experiments also revealed a significant role of TRPM7’s kinase activity in regulating the posttranslational processing of TRPM7. Utilizing the TRPM7-K1646R kinase-inactive mutant, I discovered that TRPM7 kinase inactivation leads to faster protein degradation and intracellular retention of the channel in polarized epithelial cells compared to the wildtype protein. Mutational analysis of TRPM7 autophosphorylation sites further revealed a role for S1360 as a key residue mediating both protein stability and intracellular trafficking of TRPM7. In addition, I discovered that the intrinsic kinase activity of TRPM7 mediates the interaction of the channel with the signaling protein 14-3-3θ, whose binding sites on TRPM7 also contribute to the regulation of TRPM7 trafficking. Overall, these findings expand our knowledge of the in vivo phosphorylation profile of TRPM7 and, more importantly, increase our understanding of the significance of TRPM7’s kinase for functional regulation of the channel.
Subject (authority = RUETD)
Topic
Pharmacology, Cellular and Molecular
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8751
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (ix, 128 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
TRP channels
Note (type = statement of responsibility)
by Na Cai
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3FX7DWQ
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Cai
GivenName
Na
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-04-04 15:42:30
AssociatedEntity
Name
Na Cai
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
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
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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