Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

Ozek, Ceren; Kanoski, Scott E.; Zhang, Zhong Yin; Grill, Harvey J.; Bence, Kendra K.

doi:10.1074/jbc.m114.603621

Cited by 54 publications

(47 citation statements)

References 58 publications

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“…The data also identify PTP1B as a critical of TRKB phosphorylation in Mecp2-mutant mice. Consistent with our observation, BDNF/TRKB signaling was recently shown to be augmented in the brains of PTP1B-knockout mice (52). This is of potential importance, because BDNF is also recognized as a target of MECP2 (42), thus implicating it in the etiology of RTT, and BDNF signaling is essential for various neuronal processes such as extend lifespan, would suggest that the increase in PTP1B levels that we observed in Mecp2-mutant mice would be associated with suppression of other signaling pathways in addition to the response to insulin and leptin.…”

Section: Discussionsupporting

confidence: 80%

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

Krishnan¹,

Krishnan²,

Connors³

et al. 2015

J. Clin. Invest.

101

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Section: Discussionsupporting

confidence: 80%

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

Krishnan¹,

Krishnan²,

Connors³

et al. 2015

J. Clin. Invest.

101

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“…Differential Bdnf transcription and TrkB activity could be due to increased translation of Bdnf in the striatum. Additionally, it could be due to inhibition of protein tyrosine phosphotases such as PTPRO or PTP1B, which terminate TrkB signaling (Gatto et al, 2013; Ozek et al, 2014). Phospho-TrkB returned to pre-methamphetamine levels after six weeks, irrespective of exercise status.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum

et al. 2015

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Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status.

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“…or subcutaneously (s.c.) improved behavior and motor skills in Mecp2 −/+ female mice and increased survival in Mecp2 −/y male mice. PTP1B was previously proposed to inhibit tyrosine phosphorylation of the tropomyosin receptor kinase B (TRKB) -the receptor for brain derived neurotrophic factor-, which is downregulated during RTT[11]. CPT-157633 administration increased brain TRKB Tyr phosphorylation in wild-type (WT) and Mecp2 −/+ female mice, and a substrate-trapping PTP1B mutant precipitated TRKB from mouse brain lysates, suggesting TRKB is a PTP1B substrate in the brain and that augmenting this pathway through PTP1B inhibition could be an RTT therapeutic strategy[9].…”

Section: Trends In Small-molecule Ptp Inhibitor Developmentmentioning

confidence: 99%

Targeting Tyrosine Phosphatases: Time to End the Stigma

Stanford

Bottini

2017

Trends in Pharmacological Sciences

156

147

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Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, and several PTPs have been validated as therapeutic targets for human diseases. Historically, development of drugs targeting PTPs has been highly challenging, leading to stigmatization of these enzymes as undruggable targets. Despite these difficulties, efforts to drug PTPs have persisted, and recent years have seen an influx of new probes, providing opportunities for biological examination of old and new PTP targets. Here we will discuss progress towards drugging PTPs, with special emphasis on development of selective probes with biological activity. We will describe development of new small-molecule orthosteric, allosteric and oligomerization PTP inhibitors, and discuss new studies targeting the receptor PTP subfamily with biologics.

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Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

Cited by 54 publications

References 58 publications

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum

Targeting Tyrosine Phosphatases: Time to End the Stigma

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