A Novel Role For The Adaptor Protein And Arf Gtpase-Activating Protein Cat-1/Git-1 In Cellular Transformation
| dc.contributor.author | Yoo, Sungsoo | en_US |
| dc.contributor.chair | Cerione, Richard A | en_US |
| dc.contributor.committeeMember | Crane, Brian | en_US |
| dc.contributor.committeeMember | Baird, Barbara Ann | en_US |
| dc.date.accessioned | 2013-01-31T19:44:33Z | |
| dc.date.available | 2017-12-20T07:00:24Z | |
| dc.date.issued | 2012-08-20 | en_US |
| dc.description.abstract | Cat-1/Git-1 is a multi-functional protein that acts as a GAP (GTPase-activating protein) for Arf GTPases, as well as serves as a scaffold for a number of different signaling proteins. Cat-1 is best known for its role in regulating cell shape and promoting cell migration. However, whether Cat-1 might also contribute to cellular transformation is currently unknown. Here we show that ~95% of cervical tumor samples examined over-express Cat-1, suggesting that the up-regulation of Cat-1 expression is a frequent occurrence in this type of cancer. We further demonstrate that knocking-down Cat-1 from NIH3T3 fibroblasts expressing an activated form of Cdc42 (Cdc42 F28L), or from the human cervical carcinoma (HeLa) cell line, inhibits the ability of these cells to form colonies in soft agar, an in vitro measure of tumorgenicity. The requirement for Cat-1 in the anchorage-independent growth of HeLa cells is dependent on its ability to bind paxillin, while its Arf-GAP activity had a negative effect. Collectively, these results suggested that Cat may be acting as an effector for activated Arf GTPases in promoting cellular transformation, and the binding of Cat to paxillin is a critical step in mediating the effector function. In support of this idea, the co-expression of Cat-1 and an activated form of Arf6 in fibroblasts was sufficient to induce transformation in normal NIH3T3 fibroblasts. These findings highlight novel roles for Cat-1 and its interactions with the Arf GTPases and paxillin in oncogenic transformation. ! We then go on to show that paxillin, and Hic-5, a close homolog of paxillin that also binds to Cat, act to negatively regulate the anchorage-independent growth of HeLa cervical carcinoma cell line as read-out by soft agar assay. Also, we show that binding of Cat to paxillin, but not Hic-5, is the critical function of Cat that is important for mediating the role of Cat in promoting anchorage-independent growth. These findings suggested that Cat promotes cellular transformation by binding to paxillin to block paxillin from negatively regulating cellular transformation. ! | en_US |
| dc.identifier.other | bibid: 7959920 | |
| dc.identifier.uri | https://hdl.handle.net/1813/31160 | |
| dc.language.iso | en_US | en_US |
| dc.subject | Cat-1 | en_US |
| dc.subject | Git1 | en_US |
| dc.subject | transformation | en_US |
| dc.subject | paxillin | en_US |
| dc.subject | Arf GTPase | en_US |
| dc.title | A Novel Role For The Adaptor Protein And Arf Gtpase-Activating Protein Cat-1/Git-1 In Cellular Transformation | en_US |
| dc.type | dissertation or thesis | en_US |
| thesis.degree.discipline | Chemistry and Chemical Biology | |
| thesis.degree.grantor | Cornell University | en_US |
| thesis.degree.level | Doctor of Philosophy | |
| thesis.degree.name | Ph. D., Chemistry and Chemical Biology |
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