scholarly journals A novel receptor-type protein tyrosine phosphatase with a single catalytic domain is specifically expressed in mouse brain

1995 ◽  
Vol 305 (2) ◽  
pp. 499-504 ◽  
Author(s):  
W Hendriks ◽  
J Schepens ◽  
C Brugman ◽  
P Zeeuwen ◽  
B Wieringa
Keyword(s):  
Mouse Brain ◽  
Tyrosine Kinases ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Pcr Amplification ◽  
Phosphatase Domain ◽  
Protein Tyrosine ◽  
The Brain

Protein tyrosine phosphatases (PTPases) are important regulatory proteins that, together with protein tyrosine kinases, determine the phosphotyrosine levels in cell signalling proteins. By PCR amplification of mouse brain cDNA fragments encoding the catalytic domains of these enzymes, we identified three novel members of the PTPase gene family. Northern-blot analysis showed that two of these novel clones represent brain-specific PTPases, whereas the third originates from a large-sized mRNA that is more ubiquitously expressed. A full-length cDNA encoding one of the brain-specific PTPases, PTP-SL, was isolated. Sequence analysis revealed a transmembrane PTPase containing a single catalytic phosphatase domain that has 45% homology to a rat cytoplasmic brain-specific PTPase named STEP. This suggests a role for PTP-SL in cell-cell signalling processes in the brain.

scholarly journals Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP)

2021 ◽  
Vol 22 (9) ◽  
pp. 4417
Author(s):  
Lester J Lambert ◽  
Stefan Grotegut ◽  
Maria Celeridad ◽  
Palak Gosalia ◽  
Laurent JS De Backer ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Tyrosine Kinases ◽  
High Throughput Screening ◽  
Kinase Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Synaptic Function ◽  
Label Free ◽  
Protein Tyrosine

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.

scholarly journals Protein tyrosine phosphatases and signalling

2005 ◽  
Vol 185 (1) ◽  
pp. 19-33 ◽  
Author(s):  
Andrew W Stoker
Keyword(s):  
Tyrosine Kinases ◽  
Current Knowledge ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Kinases ◽  
Tyrosine Phosphatases ◽  
Large Protein ◽  
Protein Tyrosine ◽  
Wide Range

A cornerstone of many cell-signalling events rests on reversible phosphorylation of tyrosine residues on proteins. The reversibility relies on the coordinated actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), both of which exist as large protein families. This review focuses on the rapidly evolving field of the PTPs. We now know that rather than simply scavenging phosphotyrosine, the PTPs specifically regulate a wide range of signalling pathways. To illustrate this and to highlight current areas of agreement and contention in the field, this review will present our understanding of PTP action in selected areas and will present current knowledge surrounding the regulatory mechanisms that control PTP enzymes themselves. It will be seen that PTPs control diverse processes such as focal adhesion dynamics, cell–cell adhesion and insulin signalling, and their own actions are in turn regulated by dimerisation, phosphorylation and reversible oxidation.

scholarly journals RPTPμ tyrosine phosphatase promotes adipogenic differentiation via modulation of p120 catenin phosphorylation

2011 ◽  
Vol 22 (24) ◽  
pp. 4883-4891 ◽  
Author(s):  
Won Kon Kim ◽  
Hyeyun Jung ◽  
Eun Young Kim ◽  
Do Hyung Kim ◽  
Yee Sook Cho ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Adipocyte Differentiation ◽  
Adipogenic Differentiation ◽  
Tyrosine Phosphatase ◽  
Ectopic Expression ◽  
Protein Tyrosine Phosphatases ◽  
P120 Catenin ◽  
Protein Tyrosine ◽  
Functional Roles ◽  
Novel Target

Adipocyte differentiation can be regulated by the combined activity of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). In particular, PTPs act as key regulators in differentiation-associated signaling pathways. We recently found that receptor-type PTPμ (RPTPμ) expression is markedly increased during the adipogenic differentiation of 3T3-L1 preadipocytes and mesenchymal stem cells. Here, we investigate the functional roles of RPTPμ and the mechanism of its involvement in the regulation of signal transduction during adipogenesis of 3T3-L1 cells. Depletion of endogenous RPTPμ by RNA interference significantly inhibited adipogenic differentiation, whereas RPTPμ overexpression led to an increase in adipogenic differentiation. Ectopic expression of p120 catenin suppressed adipocyte differentiation, and the decrease in adipogenesis by p120 catenin was recovered by introducing RPTPμ. Moreover, RPTPμ induced a decrease in the cytoplasmic p120 catenin expression by reducing its tyrosine phosphorylation level, consequently leading to enhanced translocation of Glut-4 to the plasma membrane. On the basis of these results, we propose that RPTPμ acts as a positive regulator of adipogenesis by modulating the cytoplasmic p120 catenin level. Our data conclusively demonstrate that differentiation into adipocytes is controlled by RPTPμ, supporting the utility of RPTPμ and p120 catenin as novel target proteins for the treatment of obesity.

scholarly journals Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Dimitrios Angelis ◽  
Maria Delivoria-Papadopoulos
Keyword(s):  
Posttranslational Modifications ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Tyrosine Phosphatase ◽  
Src Kinase ◽  
Protein Tyrosine Phosphatases ◽  
Kinase Inhibition ◽  
Protein Tyrosine ◽  
Newborn Piglets ◽  
Ptp 1B

Background. Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks.Methods. Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO20.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2for 1 hour and PTP-1B expression was measured via immunoblotting.Results. PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression.Conclusions. Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

EXPERIMENTAL AND THEORETICAL STUDY OF THE MOVEMENT OF THE WPD FLEXIBLE LOOP OF HUMAN PROTEIN TYROSINE PHOSPHATASE PTP1B IN COMPLEX WITH HALIDE IONS

2012 ◽  
Vol 07 (03n04) ◽  
pp. 197-217
Author(s):  
ALINE KATZ ◽  
PATRICIA SAENZ-MÉNDEZ ◽  
ALEXANDRA COUSIDO-SIAH ◽  
ALBERTO D. PODJARNY ◽  
OSCAR N. VENTURA
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Enzymatic Catalysis ◽  
Protein Tyrosine Phosphatases ◽  
Md Simulations ◽  
Crystallographic Structure ◽  
Halide Ions ◽  
Post Translational Modification ◽  
Protein Tyrosine

Protein tyrosine phosphorylation is a post-translational modification mechanism, crucial for the regulation of nearly all aspects of cell life. This dynamic, reversible process is regulated by the balanced opposing activity of protein tyrosine kinases and protein tyrosine phosphatases. In particular, the protein tyrosine phosphatase 1B (PTP1B) is implicated in the regulation of the insulin-receptor activity, leptin-stimulated signal transduction pathways and other clinically relevant metabolic routes, and it has been found overexpressed or overregulated in human breasts, colon and ovary cancers. The WPD loop of the enzyme presents an inherent flexibility, and it plays a fundamental role in the enzymatic catalysis, turning it into a potential target in the design of new efficient PTP1B inhibitors. In order to determine the interactions that control the spatial conformation adopted by the WPD loop, complexes between the enzyme and halide ions ( Br- and I- in particular) were crystallized and their crystallographic structure determined, and the collective movements of the aforementioned complexes were studied through Molecular Dynamics (MD) simulations. Both studies yielded concordant results, indicating the existence of a relationship between the identity of the ion present in the complex and the strength of the interactions it establishes with the surrounding protein residues.

scholarly journals Constitutive secretion of serum albumin requires reversible protein tyrosine phosphorylation events in trans-Golgi

2005 ◽  
Vol 289 (3) ◽  
pp. C748-C756 ◽  
Author(s):  
Rachel J. Webb ◽  
Jacob D. Judah ◽  
Lee-Chiang Lo ◽  
Geraint M. H. Thomas
Keyword(s):  
Serum Albumin ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphorylation ◽  
Albumin Secretion ◽  
Protein Tyrosine ◽  
Constitutive Secretion

Serum albumin secretion from rat hepatocytes proceeds via the constitutive pathway. Although much is known about the role of protein tyrosine phosphorylation in regulated secretion, nothing is known about its function in the constitutive process. Here we show that albumin secretion is inhibited by the tyrosine kinase inhibitor genistein but relatively insensitive to subtype-selective inhibitors or treatments. Secretion is also blocked in a physiologically identical manner by the tyrosine phosphatase inhibitors pervanadate and bisperoxo(1,10-phenanthroline)-oxovanadate. Inhibition of either the kinase(s) or phosphatase(s) leads to the accumulation of albumin between the trans-Golgi and the plasma membrane, whereas the immediate precursor proalbumin builds up in a proximal compartment. The trans-Golgi marker TGN38 is rapidly dispersed under conditions that inhibit tyrosine phosphatase action, whereas the distribution of the cis-Golgi marker GM130 is insensitive to genistein or pervanadate. By using a specifically reactive biotinylation probe, we detected protein tyrosine phosphatases in highly purified rat liver Golgi membranes. These membranes also contain both endogenous tyrosine kinases and their substrates, indicating that enzymes and substrates for reversible tyrosine phosphorylation are normal membrane-resident components of this trafficking compartment. In the absence of perturbation of actin filaments and microtubules, we conclude that reversible protein tyrosine phosphorylation in the trans-Golgi network is essential for albumin secretion and propose that the constitutive secretion of albumin is in fact a regulated process.

scholarly journals The Second Catalytic Domain of Protein Tyrosine Phosphatase δ (PTPδ) Binds to and Inhibits the First Catalytic Domain of PTPς

1998 ◽  
Vol 18 (5) ◽  
pp. 2608-2616 ◽  
Author(s):  
Megan J. Wallace ◽  
Christopher Fladd ◽  
Jane Batt ◽  
Daniela Rotin
Keyword(s):  
Mammalian Cells ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Regulatory Function ◽  
Yeast Two Hybrid ◽  
Protein Tyrosine ◽  
Catalytic Domains ◽  
Two Hybrid

ABSTRACT The LAR family protein tyrosine phosphatases (PTPs), including LAR, PTPδ, and PTPς, are transmembrane proteins composed of a cell adhesion molecule-like ectodomain and two cytoplasmic catalytic domains: active D1 and inactive D2. We performed a yeast two-hybrid screen with the first catalytic domain of PTPς (PTPς-D1) as bait to identify interacting regulatory proteins. Using this screen, we identified the second catalytic domain of PTPδ (PTPδ-D2) as an interactor of PTPς-D1. Both yeast two-hybrid binding assays and coprecipitation from mammalian cells revealed strong binding between PTPς-D1 and PTPδ-D2, an association which required the presence of the wedge sequence in PTPς-D1, a sequence recently shown to mediate D1-D1 homodimerization in the phosphatase RPTPα. This interaction was not reciprocal, as PTPδ-D1 did not bind PTPς-D2. Addition of a glutathione S-transferase (GST)–PTPδ-D2 fusion protein (but not GST alone) to GST–PTPς-D1 led to ∼50% inhibition of the catalytic activity of PTPς-D1, as determined by an in vitro phosphatase assay againstp-nitrophenylphosphate. A similar inhibition of PTPς-D1 activity was obtained with coimmunoprecipitated PTPδ-D2. Interestingly, the second catalytic domains of LAR (LAR-D2) and PTPς (PTPς-D2), very similar in sequence to PTPδ-D2, bound poorly to PTPς-D1. PTPδ-D1 and LAR-D1 were also able to bind PTPδ-D2, but more weakly than PTPς-D1, with a binding hierarchy of PTPς-D1>>PTPδ-D1>LAR-D1. These results suggest that association between PTPς-D1 and PTPδ-D2, possibly via receptor heterodimerization, provides a negative regulatory function and that the second catalytic domains of this and likely other receptor PTPs, which are often inactive, may function instead to regulate the activity of the first catalytic domains.

scholarly journals THE CROONIAN LECTURE 1997. The phosphorylation of proteins on tyrosine: its role in cell growth and disease

1998 ◽  
Vol 353 (1368) ◽  
pp. 583-605 ◽  
Author(s):  
Tony Hunter
Keyword(s):  
Tyrosine Kinases ◽  
Homo Sapiens ◽  
Tyrosine Phosphatase ◽  
Cell Cycle Control ◽  
Control Cell ◽  
Growth Control ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Kinases ◽  
Protein Tyrosine ◽  
Phosphorylation Of Proteins

The reversible phosphorylation of tyrosines in proteins plays a key role in regulating many different processes in eukaryotic organisms, such as growth control, cell cycle control, differentiation, cell shape and movement, gene transcription, synaptic transmission, and insulin action. Phosphorylation of proteins is brought about by enzymes called protein–tyrosine kinases that add phosphate to specific tyrosines in target proteins; phosphate is removed from phosphorylated tyrosines by enzymes called protein–tyrosine phosphatases. Phosphorylated tyrosines are recognized by specialized binding domains on other proteins, and such interactions are used to initiate intracellular signalling pathways. Currently, more than 95 protein–tyrosine kinases and more than 55 protein–tyrosine phosphatase genes are known in Homo sapiens . Aberrant tyrosine phosphorylation is a hallmark of many types of cancer and other human diseases. Drugs are being developed that antagonize the responsible protein–tyrosine kinases and phosphatases in order to combat these diseases.

Cloning and Characterization of a Lymphoid-Specific, Inducible Human Protein Tyrosine Phosphatase, Lyp

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 2013-2024 ◽  
Author(s):  
Shai Cohen ◽  
Harjit Dadi ◽  
Ester Shaoul ◽  
Nigel Sharfe ◽  
Chaim M. Roifman
Keyword(s):  
T Cells ◽  
Tyrosine Phosphorylation ◽  
Protein Kinases ◽  
Cell Activation ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Control Cell ◽  
Protein Tyrosine Phosphatases ◽  
Lymphoid Tissues ◽  
Protein Tyrosine

Protein tyrosine phosphatases act in conjunction with protein kinases to regulate the tyrosine phosphorylation events that control cell activation and differentiation. We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain. The noncatalytic domain contains four proline-rich potential SH3 domain binding sites and an NXXY motif that, if phosphorylated, may be recognized by phosphotyrosine binding (PTB) domains. Comparison of the Lyp amino acid sequence with other known proteins shows 70% identity with the murine phosphatase PEP. The human Lyp gene was localized to chromosome 1p13 by fluorescence in situ hybridization analysis. We also identified an alternative spliced form of Lyp RNA, Lyp2. This isoform encodes a smaller 85-kD protein with an alternative C-terminus. The lyp phosphatases are predominantly expressed in lymphoid tissues and cells, with Lyp1 being highly expressed in thymocytes and both mature B and T cells. Increased Lyp1 expression can be induced by activation of resting peripheral T lymphocytes with phytohemagglutinin or anti-CD3. Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells. Overexpression of lyp1 reduces Cbl tyrosine phosphorylation, suggesting that it may be a substrate of the phosphatase. Thus, Lyp may play a role in regulating the function of Cbl and its associated protein kinases.

scholarly journals Molecular cloning and expression of a unique receptor-like protein-tyrosine-phosphatase in the leucocyte-common-antigen-related phosphatase family

1994 ◽  
Vol 302 (1) ◽  
pp. 39-47 ◽  
Author(s):  
W R Zhang ◽  
N Hashimoto ◽  
F Ahmad ◽  
W Ding ◽  
B J Goldstein
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Cloning And Expression ◽  
Common Antigen ◽  
Protein Tyrosine ◽  
Receptor Targets

Protein-tyrosine-phosphatases (PTPases) have been implicated in the regulation of certain tyrosine kinase growth factor receptors in that they dephosphorylate the activated (autophosphorylated) form of the receptors. In order to identify PTPases that potentially act on receptor targets in liver, we used the human leucocyte common antigen-related PTPase (LAR) cDNA [Streuli, Krueger, Hall, Schlossman and Saito (1988) J. Exp. Med. 168, 1523-1530] and isolated two closely related transmembrane PTPase homologues from a rat hepatic cDNA library. Both PTPases had large extracellular domains that contained three immunoglobulin-like repeats and eight type-III fibronectin repeats. Both enzymes had tandem homologous PTPase domains following a single hydrophobic transmembrane domain. One sequence encoded the rat homologue of LAR. The second PTPase, designated LAR-PTP2, had 79 and 90% identity with rat LAR in the respective cytoplasmic PTPase domains, with only 57% sequence similarity in the extracellular domain. The catalytic domains of LAR and LAR-PTP2 prepared by bacterial expression were active in dephosphorylating a variety of phosphotyrosyl substrates but did not hydrolyse phosphoserine or phosphothreonine residues of labelled casein. Both enzymes exhibited rapid turnover numbers of 4-7 s-1 for myelin basic protein and 78-150 s-1 for derivatized lysozyme. LAR and LAR-PTP2 displayed similar PTPase activity towards the simultaneous dephosphorylation of receptors of intact insulin and epidermal growth factor from liver membranes. These data indicate that there is a family of LAR-related PTPases that may regulate the phosphorylation state of receptor tyrosine kinases in liver and other tissues.

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