Disease relevance of Ptpn2

• The three genotypes (+/+, +/-, -/-) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3-5 wk of age, displaying runting, splenomegaly, and lymphadenopathy [1].
• The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor [2].
• In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease [3].
• MPTP toxicity: implications for research in Parkinson's disease [4].
• In summary, the parkinsonism induced by MPTP in man closely resembles time-telescoped Parkinson's disease [4].

Psychiatry related information on Ptpn2

• Here, we investigated the effects of cystamine, which has shown neuroprotection in animal models of Huntington's disease, in a parkinsonian mouse generated by the toxin MPTP [5].
• However, during the next 5 days, motor activity returned to baseline, even with continued MPTP treatment [6].
• Injection of a low dose of haloperidol, that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice [7].
• Electroconvulsive shock does not modify striatal contents of dopamine in MPTP-treated mice [8].

High impact information on Ptpn2

• PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively [9].
• Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS) [10].
• MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease [10].
• This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease [10].
• In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites [11].

Chemical compound and disease context of Ptpn2

• In this issue of Neuron, Kaur et al. demonstrate that iron chelation by ferritin transgene or the metal chelator clioquinol prevent oxidative damage and MPTP toxicity in mice [12].
• Benztropine inhibits toxicity of MPTP in mice [13].
• MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits selective destruction of nigrostriatal dopamine neurons in humans and animals along with clinical symptoms of parkinsonism [14].
• Reduced MPTP toxicity in noradrenaline transporter knockout mice [15].
• Differential protection against MPTP or methamphetamine toxicity in dopamine neurons by deletion of ppN/OFQ expression [16].

Biological context of Ptpn2

• Fivefold-higher ligand-induced receptor phosphorylation was observed in TC-PTP ko mouse embryo fibroblasts (MEFs) as well [17].
• By measuring insulin-sensitive reporter gene expression and plasma glucose of diabetic mice, we found siRNA of PTP1B or TCPTP alone can sensitize insulin signal transduction, but combined treatment of both siRNAs had no better effects than siRNA of PTP1B [18].
• Effects of small interference RNA against PTP1B and TCPTP on insulin signaling pathway in mouse liver: Evidence for non-synergetic cooperation [18].
• This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function [1].
• TC45 inhibited the proliferation and anchorage-independent growth of Delta EGFR cells but TC45-D182A only inhibited cellular proliferation [2].

Anatomical context of Ptpn2

• The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown [1].
• BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency [1].
• Moreover, hyperosmotic stress did not induce the cytoplasmic accumulation of a green fluorescent protein-TC45 fusion protein that was too large to diffuse across the nuclear pore [19].
• In this study we have examined the intracellular distribution of TC-PTP in a glial cell line (C6) [20].
• High levels of detergent-soluble tyrosine phosphatase were measured in the particular fraction of pancreatic islets with a substrate preferred by PTP1B/TCPTP-type protein tyrosine phosphatases [21].

Associations of Ptpn2 with chemical compounds

• In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors [17].
• The hyperosmotic stress-induced nuclear exit of TC45 was not inhibited by leptomycin B, indicating that TC45 nuclear exit was independent of the exportin CRM-1 [19].
• Differential intracellular compartmentalization of phosphotyrosine phosphatases in a glial cell line: TC-PTP versus PTP-1B [20].
• MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD [22].
• In vitro TGF-beta protects neurons from damage induced by treatment with beta-amyloid peptide, FeSO4 (induces production of reactive oxygen species), Ca2+ ionophores, glutamate, glutamate receptor agonists and MPTP (toxic for dopaminergic neurons) [23].

Enzymatic interactions of Ptpn2

• In the cytoplasm, TC45 dephosphorylated the epidermal growth factor receptor and down-regulated the hyperosmotic stress-induced activation of the c-Jun N-terminal kinase [19].

Regulatory relationships of Ptpn2

• Two closely-related protein tyrosine phosphatases, PTP1B and TCPTP both showed abilities to negatively regulate insulin receptor signaling [18].

Other interactions of Ptpn2

• In order to test whether these two phosphatases can act synergistically, hydrodynamic injection was applied to deliver small interfering RNA (siRNA) of PTP1B and/or TCPTP to mouse liver [18].
• The number of CSF-1-dependent CFU is increased in Tcptp-/- bone marrow [24].
• Furthermore, we have identified the CSF-1 receptor (CSF-1R) as a physiological target of Tcptp through substrate-trapping experiments and its hyperphosphorylation in Tcptp-/- macrophages [24].
• RESULTS: We have identified two members of the Janus family of tyrosine kinases (JAKs), JAK1 and JAK3, as bona fide substrates of TCPTP [25].
• Inherent substrate specificity in the TCPTP-JAK interaction is demonstrated by the inability of other closely related PTP family members to form an in vivo interaction with the JAKs in hematopoietic cells [25].

Analytical, diagnostic and therapeutic context of Ptpn2

• In situ hybridization of brain samples revealed that MPTP delta mRNA is present in the hippocampus, thalamic reticular nucleus, and piriform cortex, where some Src family PTKs have been also demonstrated to exist [26].
• Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF beta-receptors colocalized with Rab4a, a marker for rapid recycling [27].
• Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases [28].
• In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP concentrations similar to those measured after treatment with 20 mg/kg MPTP alone [29].
• After oral administration in MPTP-treated mice, V-10,367 completely protected against MPTP-induced loss of striatal TH+ axonal density, while FK506 did not [30].

References