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dc.contributor.advisor Wang, Xiao-Fan en_US
dc.contributor.author Liu, Irwin en_US
dc.date.accessioned 2009-01-02T16:24:45Z
dc.date.available 2011-07-26T04:30:03Z
dc.date.issued 2008-12-10 en_US
dc.identifier.uri http://hdl.handle.net/10161/893
dc.description Dissertation en_US
dc.description.abstract <p>During the course of breast cancer progression, normally dormant tumor-promoting effects of transforming growth factor-beta (TGF-beta) including migration, invasion, and metastasis are unmasked. Although this switch or gain of TGF-beta function has been modeled extensively in in-vivo and in-vitro breast cancer systems, the signaling mechanisms that control this TGF-beta switch are poorly understood. Indeed, the precise role of canonical TGF-beta signaling through the type I TGF-beta receptor, ALK5, and its intracellular effectors, Smad2 and Smad3, is still poorly understood. In an effort to identify mechanisms that regulate the ability of TGF-beta to stimulate mammary epithelial cell migration in-vitro, we found that TGF-beta stimulates the phosphorylation of Smad1 and Smad5, intracellular effectors that are typically associated with bone morphogenetic protein (BMP) signaling. As this phosphorylation response has not been reported extensively, little is known about the prevalance, mechanism, function, or pathological relevance of TGF-beta-stimulated Smad1/5 phosphorylation.</p><p>Herein, we use pharmacologic inhibition, RNA interference, and additional biochemical and cell-based approaches to identify a novel mechanism and function for non-canonical TGF-beta signaling through an ALK5-Smad1/5 axis. We show that TGF-beta stimulates Smad1/5 phosphorylation in an ALK5 dependent manner in cells of epithelial, endothelial, and embryonic origin. Mechanistically, this phosphorylation event requires the kinase activity and, unexpectedly, the L45 loop motif of ALK5. Functionally, this phosphorylation event is essential to the initiation and promotion of TGF-beta-stimulated migration in mammary epithelial cells. Interestingly, this phosphorylation event may promote migration by regulating TGF-beta target gene expression, as evidenced by the identification of putative Smad1/5-dependent TGF-beta target genes using microarray analysis. Finally, of particular relevance to mammary tumor progression, this phosphorylation event is preferentially detected in permissive environments such as those created by tumorigenic cells or HER2 oncogene activation.</p><p>Taken together, our data provides evidence that TGF-beta-stimulated Smad1/5 phosphorylation, which occurs through a non-canonical mechanism that challenges the notion of selective Smad phosphorylation by ALK5, mediates the pro-migratory TGF-beta switch in mammary epithelial cells.</p> en_US
dc.format.extent 2807392 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Molecular en_US
dc.subject Biology, Cell en_US
dc.subject tgf en_US
dc.subject beta en_US
dc.subject smad en_US
dc.subject smad en_US
dc.subject migration en_US
dc.subject her en_US
dc.subject Breast-Cancer en_US
dc.title A Mechanism and Pro-migratory Function for Non-canonical TGF-beta Signaling through Smad1 and Smad5 en_US
dc.type Dissertation en_US
dc.department Pharmacology en_US
duke.embargo.months 24 en_US

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