Date of Award
Chemistry and Biochemistry
Biotechnology, Enzymology, Mass spectrometry, Proteomics, Intracellular function
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Human hYVH1, also referred to as DUSP12, is a dual specificity protein tyrosine phosphatase that is highly conserved across species and has been demonstrated to be overexpressed in various cancerous states. Prior investigation of hYVH1 has implicated it in numerous cellular functions including stress response, cell survival, and cell cycle modulation. Recently, novel evidence has suggested that hYVH1 also plays a role in ribosome biogenesis, functioning in the maturation of the pre-60S ribosomal subunit by mediating its nuclear export and the ejection of Mrt4.Additionally, the well characterized tyrosine kinase Src has been suggested to trigger hYVH1 to localize into the nucleus through strategic phosphorylation, but this event has not yet been confirmed directly through in vitro studies.
In this study, we unambiguously demonstrate that Src kinase can directly target hYVH1 for phosphorylation at the critical phosphorylation site Tyr179 through the development of an in vitro kinase assay and mass spectrometry. Further investigation into the impact of the Src-directed phosphorylation event suggested that the post-translational modification of hYVH1 triggers a decrease in hYVH1’s catalytic activity as well as an increase in hYVH1’s ribosomal biogenesis capabilities. Additionally, application of a mild hydrogen peroxide induced oxidative stressor led to the alteration of hYVH1’s ribosome biogenesis function and its ability to bind with Hsp70, a known binding partner.5 Collectively, these findings led us to propose that Src-directed phosphorylation of unbound hYVH1 is necessary for proper ribosome biogenesis to occur and that mild oxidative stress can modulate this by altering the ability of Src kinase to attenuate the formation of the hYVH1-Hsp70 complex.
Lotze, Griffin, "Exploring the Impact of Src-Directed Phosphorylation on hYVH1’s Intracellular Function" (2023). Electronic Theses and Dissertations. 9111.