Pyrimidine Nucleoside Kinase UCK1 and TAM Receptor Tyrosine Kinase MerTK Converge on the Ubiquitin-Proteasome Pathway to Regulate EGFR
| dc.contributor.advisor | Roth, Michael G. | en |
| dc.contributor.committeeMember | White, Michael A. | en |
| dc.contributor.committeeMember | Cobb, Melanie H. | en |
| dc.contributor.committeeMember | Brown, Kathlynn C. | en |
| dc.creator | Iwuaba, Veleka Cassie | en |
| dc.date.accessioned | 2016-06-27T20:09:05Z | |
| dc.date.available | 2016-06-27T20:09:05Z | |
| dc.date.created | 2014-05 | |
| dc.date.issued | 2014-04-14 | |
| dc.date.submitted | May 2014 | |
| dc.date.updated | 2016-06-27T19:46:40Z | |
| dc.description.abstract | Oncogenic addiction to EGFR is observed in many tumor types often as a result of gene amplification and/or activating mutations. In this study, we are following up on two hits from a kinase screen, Receptor Tyrosine Kinase MerTK and Pyrimidine Nucleoside Kinase UCK1. We have discovered, that in addition to perturbing EGFR signaling and accumulation, they converge on the ubiquitin-degradation pathway in NSCLC (Non-Small Cell Lung Carcinoma). Loss of UCK1 reduces EGFR accumulation by an EGF-independent mechanism but not other ErbB family members. Additionally, UCK1 depleted cells exhibit enhanced ubiquitin depletion, PARP inactivation, caspase-3 cleavage and increased BiP expression. Data from this study demonstrates that elevated BiP is likely due to depleted cytosolic ubiquitin pools and not induction of UPR. In contrast, Mertk loss results in significant EGFR accumulation, which appears to be enhanced by activating kinase mutations in EGFR, suggesting a trafficking defect in these cell lines. This data supports previous findings that EGFR mutants evade signal desensitization by prolonged residence in sorting endosomes and constitutive internalization/recycling. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 952355642 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/3316 | |
| dc.language.iso | en_US | en |
| dc.subject | Chromosome Mapping | en |
| dc.subject | Pyrimidine Nucleosides | en |
| dc.subject | Receptor Protein-Tyrosine Kinases | en |
| dc.subject | Receptor, Epidermal Growth Factor | en |
| dc.title | Pyrimidine Nucleoside Kinase UCK1 and TAM Receptor Tyrosine Kinase MerTK Converge on the Ubiquitin-Proteasome Pathway to Regulate EGFR | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Cancer Biology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |