BYU

Abstract by Christina Egbert

Personal Infomation


Presenter's Name

Christina Egbert

Degree Level

Doctorate

Co-Authors

Tsz-Yin Chan
Logan Larsen
Kristina Kohler
Madison Frey
Julia Maxson
Clifford J Whatcott
David J Bearss
David Huang
Jeffrey Tyner

Abstract Infomation


Department

Chemistry and Biochemistry

Faculty Advisor

Joshua Andersen

Title

Identification of a unique regulatory mechanism of TNK1 via interactions with 14-3-3 and ubiquitin

Abstract

TNK1 is a poorly characterized non-receptor tyrosine kinase. Studies have indicated a role for TNK1 in driving oncogenic potential; however, the function, regulation, and substrates of TNK1 still remain unknown. To understand the regulation of TNK1, we identified a cluster of phosphorylations on TNK1 that mediate 14-3-3 binding. The binding of 14-3-3 sequesters TNK1 inactive in the cytosol. In a Ba/F3 system, disruption of this interaction with 14-3-3 allows TNK1 (TNK1 AAA) to drive lymphoid cell growth independent of growth factors while TNK1 WT has restrained activity. TNK1 uniquely has an ubiquitin association (UBA) domain, interestingly mutation of residues critical for ubiquitin association abolish TNK1 activation and oncogenic signaling. Mice injected with TNK1 AAA dependent Ba/F3 cells show increased tumor burden and morbidity compared to TNK1 WT. We identify an inhibitor of TNK1 that upon oral administration of the compound prolongs survival and reduces tumor size in mice with TNK1-driven Ba/F3 cells. Taken together, our data suggest a model in which TNK1 toggles between an inactive 14-3-3 bound state and an active state bound to ubiquitin.