Novel Heregulin-Mediated Pathways To Mammalian Target Of Rapamycin Complex 1
| dc.contributor.author | Lin, Miao-chong | en_US |
| dc.contributor.chair | Cerione, Richard A | en_US |
| dc.contributor.committeeMember | Collins, Ruth N. | en_US |
| dc.contributor.committeeMember | Baird, Barbara Ann | en_US |
| dc.date.accessioned | 2013-09-05T15:56:56Z | |
| dc.date.available | 2018-05-27T06:00:48Z | |
| dc.date.issued | 2013-05-26 | en_US |
| dc.description.abstract | Heregulin (HRG) is a growth factor that mediates the activation of ErbB2/ErbB3 receptors. Aberrant signaling of HRG and the ErbB receptors give rise to human cancer. Our laboratory has previously identified mammalian target of rapamycin (mTOR), an essential hub for growth factor and nutrient sensing, as an important intermediate in HRG-signaling. This thesis focuses on the pathways that lead to the activation of mTORC1 (mTOR complex 1) in response to HRG. First, I identified the importance of mTORC2 signaling to mTORC1 in ErbB2/HRGmediated cellular transformation in SKBR3 breast cancer cells. mTORC2 was initially identified to play a role in actin cytoskeletal remodeling, but with the discovery of novel mTORC2 targets, mTORC2 has been implicated in cellular functions such as cell proliferation, survival, and metabolism. By utilizing rapamycin and an ATP-competitive inhibitor of mTOR, INK128, I was able to differentiate between mTORC1 and mTORC2 activation by HRG. In HRG/ErbB2mediated signaling to AKT, mTORC2 is required for the phosphorylation on AKT (S473) and this precedes the activating PDK1 phosphorylation at AKT (T308). AKT phosphorylates TSC2, making TSC2 unable to function on Rheb. Rheb remains in its GTP-bound form and activates mTORC1. By performing a Rictor knock-down, which decreased mTORC2 availability in the cell, the HRG-mediated transforming capability of SKBR3 cells was reduced. Next, I took a mechanistic approach to identify how small GTPases, namely Rheb, Rac, and i Cdc42, are playing a role in HRG-mediated mTORC1 activation. Using a knock-down and rescue approach, I was able to delineate that Rac and Cdc42 are upstream of Rheb, and that they signal independently of one another to mTORC1 in this context. Additionally, I found that Dock7, a GEF for Rac and Cdc42, serves as a unique scaffold for the G-proteins and mTORC1. The most intriguing finding, however, is that Dock7 also possesses properties of a Rheb GEF. It has long been hypothesized that only a GAP is needed for the regulation of Rheb, so the identification of a putative Rheb GEF is of significant interest to the field. ii | en_US |
| dc.identifier.other | bibid: 8267435 | |
| dc.identifier.uri | https://hdl.handle.net/1813/34050 | |
| dc.language.iso | en_US | en_US |
| dc.title | Novel Heregulin-Mediated Pathways To Mammalian Target Of Rapamycin Complex 1 | en_US |
| dc.type | dissertation or thesis | en_US |
| thesis.degree.discipline | Molecular and Cell Biology | |
| thesis.degree.grantor | Cornell University | en_US |
| thesis.degree.level | Doctor of Philosophy | |
| thesis.degree.name | Ph. D., Molecular and Cell Biology |
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