Key Residues of Human Cytoplasmic Protein Tyrosine Phosphatase-A and -B for Substrate Binding and Specificity
Reversible tyrosine phosphorylation plays an important role in signaling pathways that are essential for regulating cellular growth, differentiation and metabolism. Moreover, several human diseases such as diabetes, obesity and cancers are associated with the deregulation of protein tyrosine phosphatases (PTPs). Several studies provide evidence that PTPs not only contribute to cellular differentiation, but over-expression of these molecules also leads to transformation of non-transfomed cells as well. Based on these results, designing specific PTP inhibitors may ultimately function as potential therapeutic agents to treat various diseases including cancer, diabetes, and autoimmune diseases. EphA2 is a receptor tyrosine kinase which is hypo-phosphorylated and overexpressed in many metastatic cancers. The level of phosphorylation of EphA2 is controlled by the human cytoplasmic protein tyrosine phosphatase (HCPTP), which is also overexpressed in cancers. Two low molecular weight PTP isoenzymes, HCPTP-A and HCPTP-B, are generally expressed in humans. Interestingly, HCPTP-A and -B preferentially dephosphorylate different phosphotyrosine sites related to control of EphA2 activity and downstream signaling pathways. In addition, HCPTP-A and HCPTP-B have highly different activities towards substrates including pNPP and inhibitors. However, research to determine each characteristic of HCPTP-A and HCPTP-B, has not been done. Our research aims to shed light upon the key residues of HCPTP-A and HCPTP-B for substrate binding and activity through the use of site-directed mutagenesis. Because both EphA2 and HCPTP are related to cancer, revealing key residues that control the affinity of specific substrates to HCPTP-A and -B may yield an advance in understanding the biological roles of HCPTP as well as contributing to the development of rational HCPTP inhibitors for therapeutic treatment.
Stauffacher, Purdue University.
Molecular biology|Genetics|Cellular biology|Biochemistry
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