scholarly journals Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

2018 ◽  
Vol 11 (522) ◽  
pp. eaao1591 ◽  
Author(s):  
Hong Zheng ◽  
Wen-Mei Yu ◽  
Ronald R. Waclaw ◽  
Maria I. Kontaridis ◽  
Benjamin G. Neel ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Gene Encoding

Virtual Screening, Molecular Modelling and Biochemical Studies to Exploit PF14_0660 as a Target to Identify Novel Anti-malarials

2019 ◽  
Vol 16 (4) ◽  
pp. 417-426
Author(s):  
Vimee Raturi ◽  
Kumar Abhishek ◽  
Subhashis Jana ◽  
Subhendu Sekhar Bag ◽  
Vishal Trivedi
Keyword(s):  
Virtual Screening ◽  
Phosphatase Activity ◽  
Molecular Modelling ◽  
Drug Target ◽  
Antimalarial Activity ◽  
Biochemical Study ◽  
Tyrosine Phosphatase ◽  
Host Protein ◽  
Dependent Manner ◽  
Multiple Sequence

Background: Malaria Parasite relies heavily on signal transduction pathways to control growth, the progression of the life cycle and sustaining stress for its survival. Unlike kinases, Plasmodium's phosphatome is one of the smallest and least explored for identifying drug target for clinical intervention. PF14_0660 is a putative protein present on the chromosome 14 of Plasmodium falciparum genome. Methods: Multiple sequence alignment of PF14_0660 with other known protein phosphatase indicate the presence of phosphatase motif with specific residues essential for metal binding, catalysis and providing structural stability. PF14_0660 is a mixed α/β type of protein with several β -sheet and α-helix arranged to form βαβαβα sub-structure. The surface properties of PF14_0660 is conserved with another phosphate of this family, but it profoundly diverges from the host protein tyrosine phosphatase. PF14_0660 was cloned, over-expressed and protein is exhibiting phosphatase activity in a dose-dependent manner. Docking of Heterocyclic compounds from chemical libraries into the PF14_0660 active site found nice fitting of several candidate molecules. Results: Compound PPinh6, PPinh 7 and PPinh 5 are exhibiting antimalarial activity with an IC50 of 1.4 ± 0.2µM, 3.8 ± 0.3 µM and 9.4 ± 0.6&#181M respectively. Compound PPinh 6 and PPinh 7 are inhibiting intracellular PF14_0660 phosphatase activity and killing parasite through the generation of reactive oxygen species. Conclusion: Hence, a combination of molecular modelling, virtual screening and biochemical study allowed us to explore the potentials of PF14_0660 as a drug target to design anti-malarials.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

scholarly journals A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dylan R. Rivas ◽  
Mark Vincent C. Dela Cerna ◽  
Caroline N. Smith ◽  
Shilpa Sampathi ◽  
Blaine G. Patty ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Allosteric Site ◽  
Human Embryonic Kidney Cells ◽  
Protein Tyrosine ◽  
Tumor Cell Migration ◽  
Colorectal Cancer Cells ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractProtein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

scholarly journals The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B

2021 ◽  
Vol 22 (3) ◽  
pp. 1175
Author(s):  
Ryuta Inukai ◽  
Kanako Mori ◽  
Keiko Kuwata ◽  
Chihiro Suzuki ◽  
Masatoshi Maki ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Gene ◽  
Susceptibility Gene ◽  
Target Protein ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Gene Encoding ◽  
Endosomal Sorting ◽  
Cell Death Pathways ◽  
Apoptotic Protein

Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell death pathways has remained elusive. In the present study, we found that cell death-inducing p53 target protein 1 (CDIP1), a pro-apoptotic protein, interacts with ALG-2 in a Ca2+-dependent manner. Co-immunoprecipitation analysis of GFP-fused CDIP1 (GFP-CDIP1) revealed that GFP-CDIP1 associates with tumor susceptibility gene 101 (TSG101), a known target of ALG-2 and a subunit of endosomal sorting complex required for transport-I (ESCRT-I). ESCRT-I is a heterotetrameric complex composed of TSG101, VPS28, VPS37 and MVB12/UBAP1. Of diverse ESCRT-I species originating from four VPS37 isoforms (A, B, C, and D), CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C in part through the adaptor function of ALG-2. Overexpression of GFP-CDIP1 in HEK293 cells caused caspase-3/7-mediated cell death. In addition, the cell death was enhanced by co-expression of ALG-2 and ESCRT-I, indicating that ALG-2 likely promotes CDIP1-induced cell death by promoting the association between CDIP1 and ESCRT-I. We also found that CDIP1 binds to vesicle-associated membrane protein-associated protein (VAP)A and VAPB through the two phenylalanines in an acidic tract (FFAT)-like motif in the C-terminal region of CDIP1, mutations of which resulted in reduction of CDIP1-induced cell death. Therefore, our findings suggest that different expression levels of ALG-2, ESCRT-I subunits, VAPA and VAPB may have an impact on sensitivity of anticancer drugs associated with CDIP1 expression.

scholarly journals Alteration in the Gene Encoding Protein Tyrosine Phosphatase Nonreceptor Type 6 (PTPN6/SHP1) May Contribute to Neutrophilic Dermatoses

2011 ◽  
Vol 178 (4) ◽  
pp. 1434-1441 ◽  
Author(s):  
Andrew B. Nesterovitch ◽  
Zsuzsa Gyorfy ◽  
Mark D. Hoffman ◽  
Ellen C. Moore ◽  
Nada Elbuluk ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Gene Encoding ◽  
Protein Tyrosine ◽  
Neutrophilic Dermatoses ◽  
Encoding Protein

Streptococcus sanguis-induced platelet activation involves two waves of tyrosine phosphorylation mediated by FcγRIIA and αIIbβ3

2005 ◽  
Vol 93 (05) ◽  
pp. 932-939 ◽  
Author(s):  
Caroline Pampolina ◽  
Archibald McNicol
Keyword(s):  
Signal Transduction ◽  
Platelet Aggregation ◽  
Tyrosine Phosphorylation ◽  
Platelet Activation ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Lag Phase ◽  
Dependent Manner ◽  
Protein Tyrosine ◽  
Streptococcus Sanguis

SummaryThe low-affinity IgG receptor, FcγRIIA, has been implicated in Streptococcus sanguis-induced platelet aggregation. Therefore, it is likely that signal transduction is at least partly mediated by FcγRIIA activation and a tyrosine kinase-dependent pathway. In this study the signal transduction mechanisms associated with platelet activation in response to the oral bacterium, S. sanguis were characterised. In the presence of IgG, S. sanguis strain 2017–78 caused the tyrosine phosphorylation of FcγRIIA 30s following stimulation, which led to the phosphorylation of Syk, LAT, and PLCγ2. These early events were dependent on Src family kinases but independent of either TxA2 or the engagement of the αIIbβ3 integrin. During the lag phase prior to platelet aggregation, FcγRIIA, Syk, LAT, and PLCγ2 were each dephosphorylated, but were re-phosphorylated as aggregation occurred. Platelet stimulation by 2017–78 also induced the tyrosine phosphorylation of PECAM-1, an ITIM-containing receptor that recruits protein tyrosine phosphatases. PECAM-1 co-precipitated with the protein tyrosine phosphatase SHP-1 in the lag phase. SHP-1 was also maximally tyrosine phosphorylated during this phase, suggesting a possible role for SHP-1 in the observed dephosphorylation events. As aggregation occurred, SHP-1 was dephosphorylated, while FcγRIIA, Syk, LAT, and PLCγ2 were rephosphorylated in an RGDS-sensitive, and therefore αIIbβ3-dependent, manner. Additionally, TxA2 release, 5-hydro-xytryptamine secretion and phosphatidic acid formation were all blocked by RGDS. Aspirin also abolished these events, but only partially inhibited αIIbβ3-mediated re-phosphorylation. Therefore, S.sanguis-bound IgG cross links FcγRIIA and initiates a signaling pathway that is down-regulated by PECAM-1-bound SHP-1. Subsequent engagement of αIIbβ3 leads to SHP-1 dephosphorylation permiting a second wave of signaling leading to TxA2 release and consequent platelet aggregation.

scholarly journals The Gene Encoding Human Nuclear Protein Tyrosine Phosphatase, PRL-1

1998 ◽  
Vol 273 (27) ◽  
pp. 17286-17295 ◽  
Author(s):  
Yong Peng ◽  
Anna Genin ◽  
Nancy B. Spinner ◽  
Robert H. Diamond ◽  
Rebecca Taub
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Nuclear Protein ◽  
Tyrosine Phosphatase ◽  
Gene Encoding ◽  
Protein Tyrosine
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