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Structural studies of extracellular ...

Dann, Charles Elwin, III.

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Structural studies of extracellular components of the Wnt signaling pathway.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Structural studies of extracellular components of the Wnt signaling pathway./
Author:	Dann, Charles Elwin, III.
Description:	152 p.
Notes:	Adviser: Daniel J. Leahy.
Contained By:	Dissertation Abstracts International63-03B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046438
ISBN:	0493606289

Structural studies of extracellular components of the Wnt signaling pathway.
Dann, Charles Elwin, III.

Structural studies of extracellular components of the Wnt signaling pathway. - 152 p.

Adviser: Daniel J. Leahy.

Thesis (Ph.D.)--The Johns Hopkins University, 2002.

Wnt signaling plays a vital role in the embryonic development of multicellular eukaryotes ranging from hydra to human. In addition to this crucial developmental role of Wnts, improper activation of Wnt signaling has been linked to various cancer types. My thesis work has involved primarily the study of the multiple extracellular components of the Wnt signal pathway to gain insight into signal transduction. Understanding the mechanism by which Wnt proteins signal through their cognate receptors is not only important for our basic understanding of signal transduction through the plasma membrane, but also may provide insights for the design of anticancer drugs. The number of extracellular components involved in Wnt signaling continues to grow, but currently consists of at least seven protein families including Wnts, Frizzleds (Fz), low density lipoprotein receptor related proteins (LRP), secreted Frizzled related proteins (sFRP), Dickkopfs (Dkk), Wnt inhibitory factors (WIF), and Cerberus. Writs interact initially with the Frizzled receptor followed by recruitment of the LRP coreceptor to generate an active signal. Wnt signaling becomes more complex in vertebrates with the addition of sFRPs and Dkks, proteins that modulate the Writ signal by binding directly to Wnt or LRP. Successful expression of any of these signaling proteins requires that the production be carried out in eukaryotic cell lines. A system for protein expression in Chinese hamster ovary (CHO) cells was thus developed and has led to the X-ray crystallographic structures of the cysteine-rich domain (CRD) from sFRP3 and mFz8, two Frizzled superfamily members. These structures guided CRD mutagenesis experiments that implicate a contiguous region on the Frizzled receptor surface that mediates Wnt binding and also provided the first evidence that receptor oligomerization may be a key feature of Wnt signaling. Initial structural work has been followed by successful expression of many extracellular portions of proteins in the signal cascade including mouse Wnt3a, mouse Dkks, and mouse LRP6. This work has given concrete insight into the interaction of Wnt with the Frizzled receptor and has the laid the foundation for structure determination of single proteins or multi-protein complexes of multiple extracellular components of the Wnt signal pathway.

ISBN: 0493606289Subjects--Topical Terms:

1017686
Biology, Cell.

Structural studies of extracellular components of the Wnt signaling pathway.
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100 1 $a Dann, Charles Elwin, III. $3 1251252
245 1 0 $a Structural studies of extracellular components of the Wnt signaling pathway.
300 $a 152 p.
500 $a Adviser: Daniel J. Leahy.
500 $a Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1218.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2002.
520 $a Wnt signaling plays a vital role in the embryonic development of multicellular eukaryotes ranging from hydra to human. In addition to this crucial developmental role of Wnts, improper activation of Wnt signaling has been linked to various cancer types. My thesis work has involved primarily the study of the multiple extracellular components of the Wnt signal pathway to gain insight into signal transduction. Understanding the mechanism by which Wnt proteins signal through their cognate receptors is not only important for our basic understanding of signal transduction through the plasma membrane, but also may provide insights for the design of anticancer drugs. The number of extracellular components involved in Wnt signaling continues to grow, but currently consists of at least seven protein families including Wnts, Frizzleds (Fz), low density lipoprotein receptor related proteins (LRP), secreted Frizzled related proteins (sFRP), Dickkopfs (Dkk), Wnt inhibitory factors (WIF), and Cerberus. Writs interact initially with the Frizzled receptor followed by recruitment of the LRP coreceptor to generate an active signal. Wnt signaling becomes more complex in vertebrates with the addition of sFRPs and Dkks, proteins that modulate the Writ signal by binding directly to Wnt or LRP. Successful expression of any of these signaling proteins requires that the production be carried out in eukaryotic cell lines. A system for protein expression in Chinese hamster ovary (CHO) cells was thus developed and has led to the X-ray crystallographic structures of the cysteine-rich domain (CRD) from sFRP3 and mFz8, two Frizzled superfamily members. These structures guided CRD mutagenesis experiments that implicate a contiguous region on the Frizzled receptor surface that mediates Wnt binding and also provided the first evidence that receptor oligomerization may be a key feature of Wnt signaling. Initial structural work has been followed by successful expression of many extracellular portions of proteins in the signal cascade including mouse Wnt3a, mouse Dkks, and mouse LRP6. This work has given concrete insight into the interaction of Wnt with the Frizzled receptor and has the laid the foundation for structure determination of single proteins or multi-protein complexes of multiple extracellular components of the Wnt signal pathway.
590 $a School code: 0098.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biophysics, Medical. $3 1017681
650 4 $a Chemistry, Biochemistry. $3 1017722
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710 2 0 $a The Johns Hopkins University. $3 1017431
773 0 $t Dissertation Abstracts International $g 63-03B.
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856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3046438