Protein tyrosine phosphatase alpha inhibits hypothalamic leptin receptor signaling and regulates body weight
            <i>in vivo</i>

Cohen-Sharir, Yael; Kuperman, Yael; Apelblat, Daniella; Hertog, Jeroen den; Spiegel, Ivo; Knobler, Hilla; Elson, Ari

doi:10.1096/fj.201800860rr

Cited by 4 publications

(12 citation statements)

References 52 publications

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“…C57BL/6 and BALB/c mice were purchased from the Jackson Laboratory. RPTPα KO (αKO) mice on C57BL/6 background ( 54 , 66 ) were shared by J. den Hertog (Hubrecht Institute) and bred to obtain littermate WT or αKO mice. RPTPα C469S were generated using the CRISPR knock-in approach at the National Taiwan University knockout mouse core.…”

Section: Methodsmentioning

confidence: 99%

Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts

et al. 2023

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Receptor-type protein phosphatase α (RPTPα) promotes fibroblast-dependent arthritis and fibrosis, in part, by enhancing the activation of the kinase SRC. Synovial fibroblasts lining joint tissue mediate inflammation and tissue damage, and their infiltration into adjacent tissues promotes disease progression. RPTPα includes an ectodomain and two intracellular catalytic domains (D1 and D2) and, in cancer cells, undergoes inhibitory homodimerization, which is dependent on a D1 wedge motif. Through single-molecule localization and labeled molecule interaction microscopy of migrating synovial fibroblasts, we investigated the role of RPTPα dimerization in the activation of SRC, the migration of synovial fibroblasts, and joint damage in a mouse model of arthritis. RPTPα clustered with other RPTPα and with SRC molecules in the context of actin-rich structures. A known dimerization-impairing mutation in the wedge motif (P210L/P211L) and the deletion of the D2 domain reduced RPTPα-RPTPα clustering; however, it also unexpectedly reduced RPTPα-SRC association. The same mutations also reduced recruitment of RPTPα to actin-rich structures and inhibited SRC activation and cellular migration. An antibody against the RPTPα ectodomain that prevented the clustering of RPTPα also inhibited RPTPα-SRC association and SRC activation and attenuated fibroblast migration and joint damage in arthritic mice. A catalytically inactivating RPTPα-C469S mutation protected mice from arthritis and reduced SRC activation in synovial fibroblasts. We conclude that RPTPα clustering retains it to actin-rich structures to promote SRC-mediated fibroblast migration and can be modulated through the extracellular domain.

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Section: Methodsmentioning

confidence: 99%

Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts

et al. 2023

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“…With the exception of SHP2, which promotes leptin signalling by coupling to ERK kinase, all of the other four phosphatases work by inhibiting leptin signalling, leading to leptin resistance [ 78 ]. Furthermore, increased expression of these phosphatases has also been shown to promote leptin resistance [ 79 ]. Recently, another molecular mechanism was suggested for leptin resistance through the activation of matrix metalloproteinase-2 (Mmp-2) in the hypothalamus and subsequent cleavage of the extracellular domain of the LEPR [ 80 ].…”

Section: Obesity-associated Hyperleptinaemia and Leptin Resistancementioning

confidence: 99%

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

Genchi

D’Oria

Palma

et al. 2021

IJMS

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Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

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“…GLUT1 depends on blood glucose concentration (nutrients) and ischemia (decreased blood flow and oxygen level). 34,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]…”

Section: Insulin Signallingmentioning

confidence: 99%

“…GLUT1 which enables uptake of glucose in liver cell operates, independently to the action of insulin. 34,[36][37][38][39][40][41][42][43][44][45][46][47] GLUT1 expression is mainly regulated by blood glucose concentration, cell signalling mechanisms and ischemia which is the characterised by decreased blood flow and oxygen concentration. In hypoglycaemic states, there is an upregulation of GLUT1 in tissues such as brain where it helps in providing a major source of energy.…”

Section: Irs Pmentioning

confidence: 99%

“…In hypoglycaemic states, there is an upregulation of GLUT1 in tissues such as brain where it helps in providing a major source of energy. 34,[36][37][38][39][40][41][42][43][44][45][46][47] The activation of IRS due to insulin binding to the insulin receptor (InsRb) also downregulates glutamine synthetase (GS) thus leading to an increase in the formation of glycogen which is produced and stored in the liver for future use. As shown above in Figure 3 glycogen is converted into glucose via glycogenolysis and released into the bloodstream raising the blood glucose level when concentration below ideal range.…”

Section: Irs Pmentioning

confidence: 99%

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Synthesis and drug development of small molecule inhibitors of PTP1B

Wootton

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PTP1B (Protein tyrosine phosphatase 1B) is a member of the PTP (Protein tyrosine phosphatase) family of proteins and has previously been identified as a potential therapeutic target for numerous high-profile disease states, including obesity, type II diabetes, Alzheimer’s disease and certain cancers including breast cancer. This work focuses on a means of treatment of metabolic syndrome (obesity, type II diabetes, and hypertension), by synthesising potential specific small molecule inhibitors of PTP1B that are impermeable to the blood brain barrier (BBB). Herein, druggable target sites of PTP1B were investigated computationally, to assist in the identification of possible PTP1B inhibitors, for subsequent synthesis and testing. This initially entailed the virtual docking of databases of commercially available compounds, downloaded from ZINC. The main database used, contained over 870,000,000 ‘drug-like’ compounds as defined by Lipinski’s rule of 5, which resulted in 1822 computational active site hits. The process of identifying a potential hit was comprised of two stages. Initially the software used (CrossMiner) classified a molecule as a hit if a Tanimoto ratio score of ≥ 0.7 was obtained. These initial hits then underwent visual scrutiny by which any of these ‘hits’ that predominately resided outside of the active site pocket or had motifs located within the protein were discounted and not considered true hits. The remaining computational hits were then plotted in pharmaceutically relevant chemical space, and molecules of interest were selected for further investigation based upon chemical space location, physiochemical properties, binding mode and ease of synthesis. This computational work led to an initial compound library of benzodioxanes being synthesised and tested. The main driving force behind the functionalisation and modification of the initial hit compound was the ease of synthetic conversion in addition to desirable changes from computational docking studies. The potential synthesised inhibitors were then tested for PTP activity against PTP1B and TCPTP via a yeast-based inhibitory assay where the growth rate of the co-transformed yeast cells correlates to PTP inhibitor activity. For BBB permeability assessment, a commercially available kit was utilised, that used a synthetic BBB mimic membrane. Future work aims to develop the most promising hit into a potential lead compound, thus contributing to a possible future treatment for the comorbidities of obesity.

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Protein tyrosine phosphatase alpha inhibits hypothalamic leptin receptor signaling and regulates body weight in vivo

Cited by 4 publications

References 52 publications

Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts

Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

Synthesis and drug development of small molecule inhibitors of PTP1B

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