Abstract by Kristina Kohler
Clifford J Whatcott
David J Bearss
Chemistry and Biochemistry
Ubiquitin-regulated Mechansim of TNK1 Activation in Cancer
TNK1 is a tyrosine kinase that has been implicated in both tumor suppression and oncogenic signaling. However, the mechanism by which TNK1 is regulated is unknown. One feature that distinguishes TNK1 from other kinases is the presence of a functional ubiquitin association (UBA) domain on its C-terminus. We found that this domain plays a key role in regulating TNK1 activity. We show that the TNK1 UBA has high affinity for multiple polyubiquitin linkages and is required for TNK1 localization to ubiquitin- and p62-rich puncta, in which TNK1 is highly active. Significantly, point-mutations at the ubiquitin-UBA interface not only abrogate ubiquitin binding, but also inhibit TNK1 activation and abolish TNK1-mediated transformation of Ba/F3 cells. Additionally, UBA deletion abrogates the growth of tail vein-injected Ba/F3 tumors in vivo. Together, our data suggest a model in which TNK1 UBA-ubiquitin binding locks TNK1 into an active conformation and directs its localization to perinuclear puncta. This represents, to our knowledge, a novel UBA-centric mechanism of kinase activation.