Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders

Pastor, Miryam; Fernández-Calle, Rosalía; Geronimo, Bruno Di; Vicente-Rodríguez, Marta; Zapico, José María; Gramage, Esther; Coderch, Claire; Pérez-Garcı́a, Carmen; Lasek, Amy W.; Puchades‐Carrasco, Leonor; Pineda‐Lucena, Antonio; Pascual‐Teresa, Beatriz de; Herradón, Gonzalo; Ramos, Ana

doi:10.1016/j.ejmech.2017.11.080

Cited by 29 publications

(29 citation statements)

References 56 publications

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“…5 c). To confirm the relevance of the modulatory effects of RPTPβ/ζ inhibition on LPS actions in microglial cells, we tested another inhibitor of RPTPβ/ζ: MY33-3 20 . The highest concentration of MY33-3 (10 μM) significantly limited both the LPS-induced nitrites production (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the studies designed to test the effect of pharmacological inhibition of RPTPβ/ζ on LPS-induced neuroinflammation, Wt mice were administered 60 mg/kg MY10 or vehicle (10% dehydrated ethanol, 20% polysorbate 80, 70% PEG-400) by oral gavage in a volume of approximately 0.1 ml 1 h before a single IP injection of LPS (7.5 mg/kg) or saline (control). It was previously shown that the brain to plasma ratio is 3:1 1 h after intragastric administration of 60 mg/kg MY10 20 .…”

Section: Methodsmentioning

confidence: 93%

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Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

Fernández-Calle

Galán-Llario

Gramage

et al. 2020

Sci Rep

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Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 93%

Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

Fernández-Calle

Galán-Llario

Gramage

et al. 2020

Sci Rep

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“…Blocking PTN‐PTPRZ1 signaling in animal models by shRNA or anti‐PTPRZ1 antibody potently suppressed glioblastoma tumor growth and prolonged animal survival . The selective inhibition of PTPRZ1 is a promising approach for glioma therapy .…”

Section: Discussionmentioning

confidence: 99%

A novel PTPRZ1‐ETV1 fusion in gliomas

et al. 2019

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The aggressive nature of malignant gliomas and their genetic and clinical heterogeneity present a major challenge in their diagnosis and treatment. Development of targeted therapy brought attention on detecting novel gene fusions, since they represent promising therapeutic targets (eg, TRK inhibitors in NTRK fusion‐positive tumors). Using targeted next‐generation sequencing, we prospectively analyzed 205 primary brain tumors and detected a novel PTPRZ1‐ETV1 fusion transcript in 11 of 191 (5.8%) gliomas, including nine glioblastomas, one anaplastic oligodendroglioma and one pilocytic astrocytoma. PTPRZ1‐ETV1 fusion was confirmed by RT‐PCR followed by Sanger sequencing, and in‐silico analysis predicted a potential driver role. The newly detected fusion consists of the PTPRZ1 promoter in frame with the highly conserved DNA‐binding domain of ETV1 transcription factor. The ETV1 and PTPRZ1 genes are known oncogenes, involved in processes of tumor development. ETV1 is a member of the ETS family of transcription factors, already known oncogenic drivers in Ewing sarcoma, prostate cancer and gastrointestinal stromal tumors, but not in gliomas. Its overexpression contributes to tumor growth and more aggressive tumor behavior. PTPRZ1 is already considered to be a tumor growth promoting oncogene in gliomas. In 8%–16% of gliomas, PTPRZ1 is fused to the MET oncogene, resulting in a PTPRZ1‐MET fusion, which is associated with poorer prognosis but is also a positive predictive biomarker for treatment with kinase inhibitors. In view of the oncogenic role that the two fusion partners, PTPRZ1 and ETV1, exhibit in other malignancies, PTPRZ1‐ETV1 fusion might present a novel potential therapeutic target in gliomas. Although histopathological examination of PTPRZ1‐ETV1 fusion‐positive gliomas did not reveal any specific or unique pathological features, and the follow‐up period was too short to assess prognostic value of the fusion, careful monitoring of patients and their response to therapy might provide additional insights into the prognostic and predictive value of this novel fusion.

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“…It is possible that ethanol-induced activation of ALK signaling through MDK is indirectly caused by MDK binding to and inactivating RPTPβ/ζ. Of note, systemic treatment of mice with the RPTPβ/ζ inhibitor, MY10 [110], decreased binge ethanol consumption, reduced ethanol CPP, and enhanced the sedative effect of ethanol [106,111]. Treatment of neuroblastoma cells with MY10 or ethanol increased ALK phosphorylation as expected, but combined treatment of cells with MY10 and ethanol blocked the ethanol-induced increase in ALK phosphorylation [106], which might explain how MY10 is able to reduce drinking even though it is an inhibitor of RPTPβ/ζ.…”

Section: Alkmentioning

confidence: 99%

Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder

Hamada

Lasek

2020

Neurotherapeutics

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The receptor tyrosine kinases (RTKs) are a large family of proteins that transduce extracellular signals to the inside of the cell to ultimately affect important cellular functions such as cell proliferation, survival, apoptosis, differentiation, and migration. They are expressed in the nervous system and can regulate behavior through modulation of neuronal and glial function. As a result, RTKs are implicated in neurodegenerative and psychiatric disorders such as depression and addiction. Evidence has emerged that 5 RTKs (tropomyosin-related kinase B (TrkB), RET proto-oncogene (RET), anaplastic lymphoma kinase (ALK), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR)) modulate alcohol drinking and other behaviors related to alcohol addiction. RTKs are considered highly "druggable" targets and small-molecule inhibitors of RTKs have been developed for the treatment of various conditions, particularly cancer. These kinases are therefore attractive targets for the development of new pharmacotherapies to treat alcohol use disorder (AUD). This review will examine the preclinical evidence describing TrkB, RET, ALK, FGFR, and EGFR modulation of alcohol drinking and other behaviors relevant to alcohol abuse.

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Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders

Cited by 29 publications

References 56 publications

Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

A novel PTPRZ1‐ETV1 fusion in gliomas

Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder

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