BYU

Abstract by Tsz Yin Chan

Personal Infomation


Presenter's Name

Tsz Yin Chan

Degree Level

Doctorate

Co-Authors

Christina Egbert
Logan Larsen
Kristina Kohler
Maddie Frey
Julia Maxson
David Huang
Steven Warner
David Bearss
Jeffrey Tyner

Abstract Infomation


Department

Chemistry and Biochemistry

Faculty Advisor

Joshua Andersen

Title

Negative regulation of TNK1 oncogenic tyrosine kinase activity by 14-3-3

Abstract

Our study focuses on the poorly understood tyrosine kinase non-receptor 1 (TNK1), which has been repeatedly reported to have oncogenic functions. However, the mechanism by which TNK1 is regulated and its function in cancer signaling remains unknown. To understand how TNK1 is regulated, we identified a cluster of phosphorylations on TNK1 that mediate 14-3-3 binding. 14-3-3 binding retains TNK1 in the cytosol and maintains TNK1 to be inactive. Release of TNK1 from 14-3-3 binding drives TNK1 to heavy membrane fraction, where it colocalizes with ubiquitin cluster and becomes highly active. While WT TNK1 has moderate transforming activity in a Ba/F3 cell system, remarkably, a 14-3-3 binding-defective mutant of TNK1 drives rapid transformation in Ba/F3 cells.  In vivo, mice injected via tail vein with TNK1 AAA-driven Ba/F3 cells show rapid onset of tumor burden and morbidity. Finally, we identify a small molecule scaffold that inhibits TNK1 with high potency and selectivity in vitro and in vivo. In conclusion, our data reveal a mechanism of TNK1 regulation that controls its oncogenic tyrosine kinase activity and a potential strategy for TNK1 inhibition.