Date Thesis Awarded
Honors Thesis -- Access Restricted On-Campus Only
Bachelors of Science (BS)
Shantá D. Hinton
Lisa M. Landino
Mark H. Forsyth
Proteins, the workhorses of the cell, are immensely important to biological processes in all forms of life. Cellular signaling is a vital component of cellular function in which proteins play a major role. This thesis research focuses on two distinct proteins, an oncoprotein (v-ErbA) and a pseudophosphatase (MK-STYX), and their role in responses to extracellular signals. The retroviral oncoprotein v-ErbA (p75gag-v-ErbA) is a highly mutated variant of the thyroid hormone receptor α1 (TRα1) that interferes with cellular response to thyroid hormone. v-ErbA has been observed to form punctate cytoplasmic foci reminiscent of aggresomes, perinuclear accumulations of misfolded proteins. Aggresomes have several key features; specifically, this research provides evidence that v-ErbA foci, like aggresomes, colocalize with proteasomes and mitochondria. Additionally, v-ErbA aggresome formation is dependent upon the viral Gag sequence. These studies provide evidence that v-ErbA is recruited to aggresomes, highlighting a complex mode of oncogenesis across several cellular compartments. The second protein, MK-STYX [MAPK (mitogen-activated protein kinase) phospho-serine/threonine/tyrosine-binding protein] is a pseudophosphatase member of the dual-specificity phosphatase subfamily of the PTPs (protein tyrosine phosphatases). MK-STYX lacks catalytic activity due to the absence of two key amino acids from the signature motif that are essential for phosphatase activity. MK-STYX is known to bind G3BP, an RNA-binding protein that is involved in stress granule assembly, and decreases stress granule formation. This thesis research provides evidence that MK-STYX inhibition of G3BP-induced stress granule formation is not phosphorylation-dependent; MK-STYX still decreased stress granule assembly in cells expressing a non-phosphorylatable G3BP mutant. Additionally, an active mutant of MK-STYX was able to induce stress granule assembly in cells expressing the phosphomimetic G3BP-S149E. Finally, MK-STYX is homologous to a class of phosphatases responsible for regulating MAP kinase pathways, which are involved in diverse processes of cellular growth and differentiation. In PC12 cells, a model of neuronal differentiation, MK-STYX appears to induce the formation of multiple small outgrowths in untreated cells and enhances the length of outgrowths in cells treated with NGF. This data indicates a potential role in regulation of cellular response to extracellular signals. In summary, this project elucidates the recruitment of v-ErbA to aggresomes, and the pseudophosphatase MK-STYX as a regulator of the cellular stress response and neuronal differentiation.
Munyikwa, Michelle R., "Aggravated Aggregates: The Role of a Retroviral Oncoprotein and Pseudophosphatase in Cellular Responses" (2011). Undergraduate Honors Theses. William & Mary. Paper 389.
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