Browsing by Subject "Dual Specificity Phosphatase 1"

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Open Access
Pharmacological targeting of the mitochondrial phosphatase PTPMT1.
(2009) Doughty-Shenton, Dahlia
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. 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 β-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.
Open Access
Specialized motor-driven dusp1 expression in the song systems of multiple lineages of vocal learning birds.
(PLoS One, 2012) Horita, Haruhito; Kobayashi, Masahiko; Liu, Wan-Chun; Oka, Kotaro; Jarvis, Erich D; Wada, Kazuhiro
Mechanisms for the evolution of convergent behavioral traits are largely unknown. Vocal learning is one such trait that evolved multiple times and is necessary in humans for the acquisition of spoken language. Among birds, vocal learning is evolved in songbirds, parrots, and hummingbirds. Each time similar forebrain song nuclei specialized for vocal learning and production have evolved. This finding led to the hypothesis that the behavioral and neuroanatomical convergences for vocal learning could be associated with molecular convergence. We previously found that the neural activity-induced gene dual specificity phosphatase 1 (dusp1) was up-regulated in non-vocal circuits, specifically in sensory-input neurons of the thalamus and telencephalon; however, dusp1 was not up-regulated in higher order sensory neurons or motor circuits. Here we show that song motor nuclei are an exception to this pattern. The song nuclei of species from all known vocal learning avian lineages showed motor-driven up-regulation of dusp1 expression induced by singing. There was no detectable motor-driven dusp1 expression throughout the rest of the forebrain after non-vocal motor performance. This pattern contrasts with expression of the commonly studied activity-induced gene egr1, which shows motor-driven expression in song nuclei induced by singing, but also motor-driven expression in adjacent brain regions after non-vocal motor behaviors. In the vocal non-learning avian species, we found no detectable vocalizing-driven dusp1 expression in the forebrain. These findings suggest that independent evolutions of neural systems for vocal learning were accompanied by selection for specialized motor-driven expression of the dusp1 gene in those circuits. This specialized expression of dusp1 could potentially lead to differential regulation of dusp1-modulated molecular cascades in vocal learning circuits.
Open Access
The dusp1 immediate early gene is regulated by natural stimuli predominantly in sensory input neurons.
(J Comp Neurol, 2010-07-15) Horita, Haruhito; Wada, Kazuhiro; Rivas, Miriam V; Hara, Erina; Jarvis, Erich D
Many immediate early genes (IEGs) have activity-dependent induction in a subset of brain subdivisions or neuron types. However, none have been reported yet with regulation specific to thalamic-recipient sensory neurons of the telencephalon or in the thalamic sensory input neurons themselves. Here, we report the first such gene, dual specificity phosphatase 1 (dusp1). Dusp1 is an inactivator of mitogen-activated protein kinase (MAPK), and MAPK activates expression of egr1, one of the most commonly studied IEGs, as determined in cultured cells. We found that in the brain of naturally behaving songbirds and other avian species, hearing song, seeing visual stimuli, or performing motor behavior caused high dusp1 upregulation, respectively, in auditory, visual, and somatosensory input cell populations of the thalamus and thalamic-recipient sensory neurons of the telencephalic pallium, whereas high egr1 upregulation occurred only in subsequently connected secondary and tertiary sensory neuronal populations of these same pathways. Motor behavior did not induce high levels of dusp1 expression in the motor-associated areas adjacent to song nuclei, where egr1 is upregulated in response to movement. Our analysis of dusp1 expression in mouse brain suggests similar regulation in the sensory input neurons of the thalamus and thalamic-recipient layer IV and VI neurons of the cortex. These findings suggest that dusp1 has specialized regulation to sensory input neurons of the thalamus and telencephalon; they further suggest that this regulation may serve to attenuate stimulus-induced expression of egr1 and other IEGs, leading to unique molecular properties of forebrain sensory input neurons.