Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

Abstract

<p>The dual specificity protein tyrosine phosphatases comprise the largest and most diverse group of protein tyrosine phosphatases and play integral roles in the regulation of cell signaling events. The dual specificity protein tyrosine phosphatases impact multiple cellular processes including mitogenesis, differentiation, adhesion, migration, insulin secretion and programmed cell death. Thus, the dysregulation of these enzymes has been implicated in a myriad of human disease states. While the large volume of genetic data that has become available following genome sequencing efforts over the last decade has led to the rapid identification of many new dual specificity protein tyrosine phosphatases, the elucidation of the cellular function and substrates of these enzymes has been much slower. Hence, there is a need for new tools to study the dual specificity protein tyrosine phosphatases and the identification of inhibitors of these enzymes is regarded as an attractive prospect, potentially affording not only new means of studying these enzymes, but also possible therapeutics for the treatment of diseases caused by their dysregulation. However, the identification of potent, selective inhibitors of the dual specificity protein tyrosine phosphatases has proven somewhat difficult.</p><p>PTPMT1, Protein Tyrosine Phosphatase Localized to the Mitochondrion 1 is a recently discovered, mitochondrion-localized, dual specificity phosphatase which has been implicated in the regulation of insulin secretion. However, the details of the mechanism by which PTPMT1 impacts insulin secretion, as well as its substrate in the pancreatic beta cell, have yet to be uncovered. Thus, the identification of a potent, selective inhibitor of the enzyme would aid in further study of PTPMT1. This work describes the identification of such an inhibitor of PTPMT1 following an in vitro screen of small molecule, chemical compounds using an artificial substrate. Following the screen, the lead compound emerged as a potent and potentially selective inhibitor of PTPMT1 both in vitro and in cells. Studies using this compound have shown that the compound induces increased secretion of insulin in a dose-dependent manner and thus support the notion that PTPMT1 may serve as a potential target for the treatment of Type II diabetes.</p>