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Thesis (Ph. D.)--University of Virginia, 2007. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

published_or_final_version / abstract / toc / Zoology / Master / Master of Philosophy

Graduation date: 1992

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 107-111). Available also in a digital version from Dissertation Abstracts.

One of the current goals in cancer research is to discover and validate novel molecular targets that may be useful for diagnostic and therapeutic purposes in fighting this disease. The PRL phosphatases (PRL-1, PRL-2, and PRL-3) are low molecular weight protein tyrosine phosphatases with unknown biological function(s) that have gained attention from cancer researchers in the past couple of years, mainly due to reports that these phosphatases may play important roles in tumor progression and metastasis. Motivated by the particular urgent need for molecular targets in pancreatic cancer this work was undertaken to determine what role PRL proteins played in pancreatic cancer biology and to determine if targeting PRLs would be effective in treating this disease. In this dissertation, it was found that both PRL-1 and PRL-2, but not PRL-3 are upregulated in pancreatic adenocarcinomas, suggesting that some cancer cells are dependent upon their activity for continued proliferation and survival. To validate this hypothesis, siRNAs were used in cell-based assays to evaluate the biological consequences of PRL-1 and/or PRL-2 inhibition. It was found that perturbations in PRL phosphatase signaling result in reduced proliferation, migration and especially the ability to grow in soft agar. Oligonucleotide microarray analysis revealed that many Erk and/or Akt dependent stress and growth factor inducible genes were differentially regulated between pancreatic cancer cells treated with PRL-targeting siRNA and their non-targeting siRNA treated counterparts. Subsequently, PRL knockdown was found to alter serum induced as well as amino acid deprivation induced Akt and Erk phosphorylation in multiple pancreatic cancer cell lines, suggesting that PRLs function upstream of these key pathways. Interestingly, we show that PRL proteins in cell free assays exhibit higher activity on doubly phosphorylated phosphatidylinositol substrates than tyrosine-phosphorylated peptides, suggesting that the biological substrate(s) might include non-protein molecules. These data support the hypothesis that PRL-1 and PRL-2 might play important biological roles in pancreatic cancer cells and further studies should be undertaken to determine the usefulness of these phosphatases as potential molecular biomarkers and targets.

Histidine-Domain-Protein-Tyrosine-Phosphatase (HD-PTP) has been classified as a non-transmembrane protein tyrosine phosphatase (PTP), however, its catalytic activity has not been appropriately characterized. In this thesis, the tyrosine phosphatase activity of HD-PTP was characterized. To do so, the HD-PTP protein was successfully purified using the FLAG-TAG purification system and an enzymatic assay was carried out using the DiFMUP fluorogenic substrate. My results suggest that HD-PTP is an inactive PTP that can be reactivated upon the back mutation of a conserved amino acid located in its catalytic domain motif 9, which diverges from the PTP consensus sequence. Interestingly, the gene which encodes for HD-PTP is located within the tumor suppressor region on the human chromosome 3p21.3. Furthermore, we determined through colony formation assays that the active mutation does not affect the tumor suppressor potential of HD-PTP. Although wild type HD-PTP is an inactive tyrosine phosphatase, it may act as a natural trapping mutant, thus preserving its strong binding potential for phosphorylated signaling proteins. Since the active HD-PTP mutant should have lost its ability to bind phosphorylated signaling proteins, it was used in a substrate trapping experiment to identify potential binding partners. Four putative binding partners were then purified and identified through multidimensional protein identification technique (MudPIT). Lastly, cell lines that stably express HD-PTP were generated for future studies in the identification of binding partners.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references. Also available on the World Wide Web.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Missouri-Columbia, 2004. / Typescript. Vita. Includes bibliographical references (leaves 112-125). Also available on the Internet.