Interactions of Syk and TRIP in the TNF-mediated survival pathway in breast epithelial cells
Abstract
The nonreceptor, protein-tyrosine kinase Syk has been characterized recently as a suppressor of breast cancer progression whose expression is inversely correlated with the invasive behavior of cancer cells. In contrast, Syk plays a positive role in murine mammary tumor virus-mediated tumorigenesis. To explore the pathways in which Syk participates in breast epithelial cells, I performed a yeast two-hybrid screen and identified TRAF-interacting protein (TRIP) as a novel Syk-binding partner from human mammary gland. By using an anti-TRIP antibody, I showed for the first time that endogenous TRIP is present in multiple breast epithelial cells and is localized in the nucleolus. Syk interacts with TRIP in the resting state and this interaction is enhanced by treatment with tumor necrosis factor (TNF). The interaction is mediated by the C-terminal region of TRIP and requires the kinase activity and phosphorylation of Syk at tyrosine 342 and 346. Syk and TRIP play opposing roles in intracellular pathways in response to TNF. While Syk enhances the TNF-induced activation of NF-kB, TRIP inhibits both basal and TNF-dependent NF-kB activities. In addition, TRIP is required for TNF-induced activation of caspase 8 and apoptosis. The overexpression of TRIP sensitizes cells to TNF-induced apoptosis, an effect that can be reversed by the co-expression of Syk. In summary, we have identified TRIP as a novel Syk-interacting protein and showed that Syk and TRIP have opposing effects on the TNF-induced activation of NF-kB and cell survival. These studies provide an important clue as to the mechanism by which Syk participates in the regulation of cell growth and survival in breast epithelial cells.
Degree
Ph.D.
Advisors
Geahlen, Purdue University.
Subject Area
Molecular biology|Oncology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.