Molecular underpinnings of neurodegenerative disorders: striatal-enriched protein tyrosine phosphatase signaling and synaptic plasticity

This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer’s and Parkinson’s disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity.

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STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417423112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1202-1207 ◽

Cited By ~ 34

Author(s):

Pradeep K. Kurup ◽

Jian Xu ◽

Rita Alexandra Videira ◽

Chimezie Ononenyi ◽

Graça Baltazar ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Tyrosine Phosphatase ◽

Dopaminergic Neurons ◽

Tyrosine Phosphatase ◽

E3 Ligase ◽

Substantia Nigra Pars Compacta ◽

Rat Striatum ◽

Protein Tyrosine ◽

Cellular Models

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP61 is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.

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Role of Receptor Protein Tyrosine Phosphatase β/ζ in Neuron–Microglia Communication in a Cellular Model of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22136646 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6646

Author(s):

Marta del Campo ◽

Rosalía Fernández-Calle ◽

Marta Vicente-Rodríguez ◽

Sara Martín Martínez ◽

Esther Gramage ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Neuroblastoma Cells ◽

Specific Inhibitor ◽

Receptor Protein ◽

Protein Tyrosine ◽

Receptor Protein Tyrosine Phosphatase

Pleiotrophin (PTN) is a neurotrophic factor that regulates glial responses in animal models of different types of central nervous system (CNS) injuries. PTN is upregulated in the brain in different pathologies characterized by exacerbated neuroinflammation, including Parkinson’s disease. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is abundantly expressed in the CNS. Using a specific inhibitor of RPTPβ/ζ (MY10), we aimed to assess whether the PTN/RPTPβ/ζ axis is involved in neuronal and glial injury induced by the toxin MPP+. Treatment with the RPTPβ/ζ inhibitor MY10 alone decreased the viability of both SH-SY5Y neuroblastoma cells and BV2 microglial cultures, suggesting that normal RPTPβ/ζ function is involved in neuronal and microglial viability. We observed that PTN partially decreased the cytotoxicity induced by MPP+ in SH-SY5Y cells underpinning the neuroprotective function of PTN. However, MY10 did not seem to modulate the SH-SY5Y cell loss induced by MPP+. Interestingly, we observed that media from SH-SY5Y cells treated with MPP+ and MY10 decreases microglial viability but may elicit a neuroprotective response of microglia by upregulating Ptn expression. The data suggest a neurotrophic role of microglia in response to neuronal injury through upregulation of Ptn levels.

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Therapeutic Role of Protein Tyrosine Phosphatase 1B in Parkinson’s Disease via Antineuroinflammation and Neuroprotection In Vitro and In Vivo

Parkinson s Disease ◽

10.1155/2020/8814236 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Chien-Wei Feng ◽

Nan-Fu Chen ◽

Te-Fu Chan ◽

Wu-Fu Chen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Tyrosine Phosphatase ◽

Neuronal Damage ◽

Tyrosine Phosphatase ◽

Negative Regulator ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Arginase 1

Parkinson’s disease (PD) is one of the most widespread neurodegenerative diseases. However, the currently available treatments could only relieve symptoms. Novel therapeutic targets are urgently needed. Several previous studies mentioned that protein tyrosine phosphatase 1B (PTP1B) acted as a negative regulator of the insulin signal pathway and played a significant role in the inflammation process. However, few studies have investigated the role of PTP1B in the central nervous system. Our study showed that suramin, an inhibitor of PTP1B, could improve neuronal damage. It could significantly attenuate the interferon-gamma-induced upregulation of proinflammatory cytokines, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). It enhanced M2 type microglia markers, such as arginase-1 and Ym-1 in BV2 murine microglial cells. PTP1B inhibition also reversed 6-hydroxydopamine- (6-OHDA-) induced downregulation of phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. Besides, we knocked down and overexpressed PTP1B in the SH-SY5Y cells to confirm its role in neuroprotection. We also verified the effect of suramin in the zebrafish PD model. Treatment with suramin could significantly reverse 6-OHDA-induced locomotor deficits and improved tyrosine hydroxylase (TH) via attenuating endoplasmic reticulum (ER) stress biomarkers. These results support that PTP1B could potentially regulate PD via antineuroinflammation and antiapoptotic pathways.

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Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20143407 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3407 ◽

Cited By ~ 2

Author(s):

Paola Imbriani ◽

Annalisa Tassone ◽

Maria Meringolo ◽

Giulia Ponterio ◽

Graziella Madeo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Synaptic Plasticity ◽

Mouse Model ◽

Caspase 3 ◽

Cysteine Proteases ◽

Synaptic Function ◽

Adult Brain ◽

Striatal Slices

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

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Dual Specificity Phosphatases: From Molecular Mechanisms to Biological Function

International Journal of Molecular Sciences ◽

10.3390/ijms20184372 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4372 ◽

Cited By ~ 1

Author(s):

Rafael Pulido ◽

Roland Lang

Keyword(s):

Protein Tyrosine Phosphatase ◽

Human Disease ◽

Molecular Mechanisms ◽

Biological Function ◽

Tyrosine Phosphatase ◽

Heterogeneous Group ◽

Class I ◽

Protein Tyrosine ◽

Dual Specificity ◽

Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...]

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Protein Tyrosine Phosphatase SHP-2 (PTPN11) in Hematopoiesis and Leukemogenesis

Journal of Signal Transduction ◽

10.1155/2011/195239 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Xia Liu ◽

Cheng-Kui Qu

Keyword(s):

Protein Tyrosine Phosphatase ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Tyrosine Phosphatase ◽

Hematologic Malignancies ◽

Cytokine Signaling ◽

Interacting Proteins ◽

Protein Tyrosine ◽

And Function ◽

Shed Light

SHP-2 (PTPN11), a ubiquitously expressed protein tyrosine phosphatase, is critical for hematopoietic cell development and function owing to its essential role in growth factor/cytokine signaling. More importantly, germline and somatic mutations in this phosphatase are associated with Noonan syndrome, Leopard syndrome, and childhood hematologic malignancies. The molecular mechanisms by which SHP-2 mutations induce these diseases are not fully understood, as the biochemical bases of SHP-2 functions still remain elusive. Further understanding SHP-2 signaling activities and identification of its interacting proteins/substrates will shed light on the pathogenesis of PTPN11-associated hematologic malignancies, which, in turn, may lead to novel therapeutics for these diseases.

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Regulatory Functions of Protein Tyrosine Phosphatase Receptor Type O in Immune Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.783370 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feiling Xie ◽

Hongmei Dong ◽

Hao Zhang

Keyword(s):

T Cells ◽

B Cells ◽

Immune Cells ◽

Protein Tyrosine Phosphatase ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatases ◽

Receptor Type ◽

Protein Tyrosine ◽

Cellular Processes

The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.

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The Role of Protein Tyrosine Phosphatase, Shp2, in FLT3-ITD-Induced Leukemogenesis.

Blood ◽

10.1182/blood.v112.11.1804.1804 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1804-1804

Author(s):

Sarah C Nabinger ◽

Seiji Fukuda ◽

Reuben Kapur ◽

Rebecca Chan

Keyword(s):

Protein Tyrosine Phosphatase ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Dependent Manner ◽

Erk Activation ◽

Protein Tyrosine ◽

Knock Down ◽

Mammalian Expression ◽

Tandem Duplications

Abstract Internal tandem duplications of the FMS-like receptor tyrosine kinase (FLT3-ITDs), an in-fame insertion of several amino acids within the juxtamembrane domain, are present in 25% of acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3-ITDs induce FLT3 ligand (FL)-independent hyperactivation of Erk and promiscuous activation of STAT5; however, the molecular mechanisms underlying aberrant activation of these signaling molecules is largely unknown. Tyrosine 599 (Y599) of WT FLT3 recruits the protein tyrosine phosphatase, Shp2, upon stimulation with FL, resulting Erk activation. In several FLT3-ITDs, including N51-FLT3 and N73-FLT3, Y599 is duplicated. These findings led us to hypothesize that increased recruitment of Shp2 to N51-FLT3 or N73- FLT3, via Y599, results in enhanced Shp2 activation and contributes to N51-FLT3- and N73-FLT3-induced cellular hyperproliferation, Erk hyperactivation, and promiscuous STAT5 activation. Using Baf3 cells stably expressing WT FLT3, N51-FLT3, or N73- FLT3, co-immunoprecipitation assays demonstrated that Shp2 is phosphorylated and associates with WT FLT3 in a FL-dependent manner. However, in contrast, Shp2 is constitutively hyperphosphorylated and associated with FLT3-N51 and FLT3-N73 independent of FL stimulation. To investigate the functional role of Shp2 in Flt3-ITD-induced leukemogenesis, Baf3 cells expressing WT FLT3, N51-FLT3, or N73-FLT3 were transfected with a mammalian expression vector encoding a U6 polymerase III– directed Shp2-specific short-hairpin RNA (shRNA) or a scrambled shRNA and selected in puromycin. Western blot analysis revealed significant reduction of Shp2 expression by the Shp2-specific shRNA and no change in Shp2 expression by the scrambled shRNA in all cell lines. Upon knock-down of Shp2 in Baf3/WT-FLT3 cells, proliferation was minimally reduced based on thymidine incorporation assays; however, knock-down of Shp2 in Baf3/N51-FLT3 and Baf3/N73-FLT3 cells significantly reduced proliferation, both at baseline and in response to FL stimulation. Collectively, these data suggest that constitutive recruitment of Shp2 to N51-FLT3 and N73-FLT3 contributes to the FLT3- ITD-induced hyperproliferative phenotype and imply that inhibition of Shp2 function may provide a novel therapeutic approach to FLT3-ITD-bearing leukemias.

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Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510167112 ◽

2015 ◽

Vol 112 (31) ◽

pp. E4264-E4271 ◽

Cited By ~ 16

Author(s):

Yoji Murata ◽

Takenori Kotani ◽

Yana Supriatna ◽

Yasuaki Kitamura ◽

Shinya Imada ◽

...

Keyword(s):

Epithelial Cells ◽

Tyrosine Kinase ◽

Tyrosine Phosphorylation ◽

Intestinal Epithelium ◽

Protein Tyrosine Phosphatase ◽

Molecular Mechanisms ◽

Transmembrane Protein ◽

Tyrosine Phosphatase ◽

Intestinal Immunity ◽

Protein Tyrosine

Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer–associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10–deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1–deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-κB (NF-κB). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.

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PTP-NP, a new member of the receptor protein tyrosine phosphatase family, implicated in development of nervous system and pancreatic endocrine cells

Development ◽

10.1242/dev.122.7.2239 ◽

1996 ◽

Vol 122 (7) ◽

pp. 2239-2250 ◽

Cited By ~ 5

Author(s):

M.K. Chiang ◽

J.G. Flanagan

Keyword(s):

Protein Tyrosine Phosphatase ◽

Endocrine Cells ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Receptor Protein ◽

Receptor Interaction ◽

Developmental Control ◽

Protein Tyrosine ◽

Extracellular Region ◽

Pancreatic Endocrine Cells

The regulation of protein tyrosine phosphorylation is an important mechanism for developmental control. We describe here a new member of the protein tyrosine phosphatase (PTP) family, called PTP-NP (for neural and pancreatic). The cDNA sequence indicates a receptor-type transmembrane molecule. At early organogenesis, in situ hybridization with a probe for the PTP-NP extracellular region detects expression confined to the region of the developing pancreas, an organ of medical importance, but poorly understood with regard to molecular mechanisms of developmental control. This localized expression appears early, even before morphological differentiation of the pancreas, and is found in presumptive precursors of the endocrine cells by the earliest times that they can be distinguished. In neural development, an alternate RNA with a different or missing extracellular region is expressed transiently at early stages of neurogenesis and the full-length PTP-NP RNA appears later. To search for a ligand of PTP-NP, a fusion protein probe was made with the extracellular domain fused to an alkaline phosphatase tag. This probe bound strongly to pancreatic islets, providing evidence for a ligand-receptor interaction that could be involved in endocrine cell regulation. The results show PTP-NP is an especially early marker for pancreatic development and suggest it may be a receptor that could control the development of pancreatic endocrine cells.

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