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A novel role for the adaptor protein...

University of California, Irvine.

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A novel role for the adaptor protein Grb2 in the Wnt signaling pathway.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	A novel role for the adaptor protein Grb2 in the Wnt signaling pathway./
作者:	Crampton, Steve Philip.
面頁冊數:	147 p.
附註:	Adviser: Christopher C. W. Hughes.
Contained By:	Dissertation Abstracts International69-06B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3318715
ISBN:	9780549682059

A novel role for the adaptor protein Grb2 in the Wnt signaling pathway.
Crampton, Steve Philip.

A novel role for the adaptor protein Grb2 in the Wnt signaling pathway. - 147 p.

Adviser: Christopher C. W. Hughes.

Thesis (Ph.D.)--University of California, Irvine, 2008.

Wnts are secreted glycoproteins important for a variety of biological processes such as cell proliferation, differentiation and migration. The most well characterized wnt pathway leads to the stabilization of the protein beta-catenin. Normally, cytoplasmic levels of beta-catenin are kept low because a multiprotein complex consisting of Axin, APC, and GSK3beta induces its phosphorylation and subsequent degradation. Wnt stimulation inhibits this complex, leading to stabilization, nuclear import and binding with LEF/TCF transcription factors already occupying promoter sites of wnt target genes.

ISBN: 9780549682059Subjects--Topical Terms:

1017686
Biology, Cell.

A novel role for the adaptor protein Grb2 in the Wnt signaling pathway.
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100 1 $a Crampton, Steve Philip. $3 1025259
245 1 2 $a A novel role for the adaptor protein Grb2 in the Wnt signaling pathway.
300 $a 147 p.
500 $a Adviser: Christopher C. W. Hughes.
500 $a Source: Dissertation Abstracts International, Volume: 69-06, Section: B, page: 3494.
502 $a Thesis (Ph.D.)--University of California, Irvine, 2008.
520 $a Wnts are secreted glycoproteins important for a variety of biological processes such as cell proliferation, differentiation and migration. The most well characterized wnt pathway leads to the stabilization of the protein beta-catenin. Normally, cytoplasmic levels of beta-catenin are kept low because a multiprotein complex consisting of Axin, APC, and GSK3beta induces its phosphorylation and subsequent degradation. Wnt stimulation inhibits this complex, leading to stabilization, nuclear import and binding with LEF/TCF transcription factors already occupying promoter sites of wnt target genes.
520 $a We show that the beta-catenin-dependent wnt pathway is intact in activated human T cells, and that endothelial-derived wilts drive transmigration of T cells through an endothelial monolayer in vitro and into inflamed tissue in vivo. Wnt-induced migration correlates with the direct transcriptional upregulation of the matrix metalloproteinase 2 and 9, which degrade the extracellular matrix. Finally, MMP inhibitors block wnt-induced migration, suggesting that upregulation of MMPs is required for wnt-mediated transendothelial migration.
520 $a We also define a novel role for the adaptor protein Grb2 in the beta-catenin-dependent wnt pathway. Expression of Grb2 in HEK293 cells synergizes with activators of the pathway such as wnt3a, Dishevelled, constitutively active LRP6, constitutively active beta-catenin, and LEF-1 to induce a LEF/TCF-dependent reporter. Synergy between Grb2 and LEF-1 does not require direct binding of beta-catenin to LEF-1, as an N-terminally deleted version of LEF-1 that lacks the beta-catenin-binding domain works as well as the WT protein. A dominant negative version of c-Jun (JunAA) blocks both the synergy between Grb2 and Dvl2 as well as that between Grb2 and LEF-1. Dominant negative Grb2 proteins block Wnt3a-mediated activation of the LEF/TCF-dependent reporter, suggesting that endogenous Grb2 is activated downstream of Wnt3a. The SH3 domains in Grb2 are redundant for synergy with Dvl or CA-beta-catenin but not for synergy with LEF-1, which requires both SH3 domains and the SH2 domain to be intact. Finally, Grb2 enhances CA-beta-catenin-mediated activation of the MMP9 promoter, demonstrating the importance of this pathway in T cell transmigration. These data support a role for Grb2 in the beta-catenin-dependent wnt pathway acting upstream of LEF/TCF but in parallel to Dvl and beta-catenin.
590 $a School code: 0030.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Immunology. $3 1017716
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690 $a 0379
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710 2 $a University of California, Irvine. $3 705821
773 0 $t Dissertation Abstracts International $g 69-06B.
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790 1 0 $a Hughes, Christopher C. W., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3318715