Abstract by Eranga Roshan Balasooriya Loku Balasooriyage
Eranga Roshan Balasooriya Loku Balasooriyage
Katie L pennington
jacob L Oven
Joshua L Andersen
Chemistry and Biochemistry
Regulation of the oncogenic tyrosine kinase ACK1 through a novel ubiquitin-dependent mechanism
TNK2 is an oncogene in the ACK family of non-receptor tyrosine kinases (NRTK). In humans, TNK2 is located on chromosome 3q29, a region that is frequently amplified in a variety of cancers including prostate, lung, and breast. The ACK kinase family has a unique domain arrangement with, most notably, a putative ubiquitin association (UBA) domain at their C-termini. In the present study, we focus on understanding the ubiquitin-binding nature of the ACK1/TNK2 UBA and its role in kinase regulation. In the present study, using biochemical approaches, we found that active ACK1 is associated almost exclusively within a heavy membrane cellular fraction. Deletion of the UBA untethers ACK1 from this heavy membrane fraction and abrogates ACK1 activity. Thus, the UBA is required for ACK1 activity. Our current efforts are focused on using a combination of structural and molecular approaches to understand mechanistically how the UBA controls ACK1 kinase activity. Taken together, our data suggest a model in which interaction with ubiquitin activates ACK1, which may reveal new therapeutic strategies to target ACK1 in cancer.