Stevastelins, a novel group of immunosuppressants, inhibit dual-specificity protein phosphatases

Hamaguchi, Takuya; Masuda, Akira; Morino, Tomio; Osada, Hiroyuki

doi:10.1016/s1074-5521(97)90071-5

Cited by 40 publications

(26 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously found potent and selective PTPase inhibitors, including RK-682 [36]and stevastelins [37]. Using them, we evaluated the roles of PTPases in cellular signal transduction.…”

Section: Discussionmentioning

confidence: 99%

TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

Hamaguchi

Takahashi²,

Manaka³

et al. 2001

Int Arch Allergy Immunol

Self Cite

View full text Add to dashboard Cite

Background: CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. Method: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. Results: TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. Conclusion: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases.

show abstract

“…We have previously found potent and selective PTPase inhibitors, including RK-682 [36]and stevastelins [37]. Using them, we evaluated the roles of PTPases in cellular signal transduction.…”

Section: Discussionmentioning

confidence: 99%

TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

Hamaguchi

Takahashi²,

Manaka³

et al. 2001

Int Arch Allergy Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, it is important to identify novel inhibitor of VHR phosphatase for cancer treatment. Several VHR phosphatase inhibitors including stevastelins, 7 glucosamine-aminoehoxy triphenyltin (GATPT), 8 RK-682, 9 and 4-iA 10 have been identified so far. In search for more putative VHR phosphatase inhibitors, we investigated whether 8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid (NSC-87877) has inhibitory effect on VHR phosphatase.…”

mentioning

confidence: 99%

Regulation of Vaccinia H1-related (VHR) Phosphatase Activity by NSC-87877

Park¹,

Song²,

Cho

2009

Bulletin of the Korean Chemical Society

View full text Add to dashboard Cite

Half maximal inhibitory constant of enzyme was determined to 7.83 ± 0.98 µM. VHR phosphatase (100 nM) was incubated with various concentrations of NSC-87877 at 37 o C for 30 min. Fluorescence emission from the product was measured with a multiwell plate reader as described in Experimental section.Based on amino-acid sequences of catalytic domains, protein tyrosine phosphatases (PTPs) can be classified into four groups 1 ; class I Cys-based PTPs, class II Cys-based PTPs, class III Cys-based PTPs, and Asp-based PTPs. Each PTP has a characteristic role in a variety of cellular processes including cellular metabolism, growth, proliferation, differentiation and also has been emerged as a therapeutic target in many diseases such as diabetes, leukemia, neurodegradation, and cancer. Class I PTPs comprise dual specificity phosphatases (DUSPs) including VHR that has diverse substrate specificities both or either on phospho-Tyr, phospho-Ser, and phospho-Thr residues. Class II PTPs that dephosphorylate only pTyr are encoded by a single gene ACP1 and related to diseases like Alzheimer's disease and asthma. Class III PTPs comprise CDC25 family proteins that regulate cell cycle by acting on Cdks. They dephosphorylate Thr-Tyr motifs of N-terminal Cdks, thus keep them from driving the cell progression.2 Asp-based PTPs encoded by only four Eya genes recently have been listed as a new family.VHR phosphatase, also called DUSP3, is a 20 kDa protein that might be one of the smallest known PTPs. VHR phosphatase can be elucidated by two particular characteristics in cellular physiology. First, VHR phosphatase shows more expression in the nucleus of cancer cells than that of normal cells. It is not due to the increase of transcription of VHR gene, but due to stabilization VHR phosphatase in cancer cell. Its expression was increased in cervix carcinoma and prostate cancer. 4 Another intriguing aspect of VHR phosphatase is that it fluctuates during the phases of cell cycle. VHR phosphatase during G1 phase is not detected due to rapid degradation. Gradually, it accumulates by means of its augmented transcription during late G1 and S phases. 5 The siRNA interference analyses also show that depletion of VHR phosphatase arrests cells at the G 1 /S, and G 2 /M phases. 5 Highly active extracellular signal regulated kinase (ERK) is a main reason of the cell cycle arrest. 6 Elevated VHR phosphatase expression results in cell cycle progression by dephosphorylating ERK. Due to its elevated protein level in cancers such as cervix carcinoma and prostate cancer and involvement in cell cycle progression, VHR phosphatase has been emerged as a therapeutic target. Therefore, it is important to identify novel inhibitor of VHR phosphatase for cancer treatment. Several VHR phosphatase inhibitors including stevastelins, 7 glucosamine-aminoehoxy triphenyltin (GATPT), 8 RK-682, 9 and 4-iA 10 have been identified so far. In search for more putative VHR phosphatase inhibitors, we investigated whether 8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid ...

show abstract

“…139 The stevastelins (5) represent a family of cyclic depsipeptide immunosuppressants that inhibit the dual specificity phosphatase, VHR. 140 While the sulfated derivative stevastelin A potently inhibits VHR in extracellular enzyme preparations, it has little effect in cellular preparations. The converse is true for stevastelin B, which lacks the threonyl sulfate group.…”

Section: Natural Product-derived Inhibitorsmentioning

confidence: 99%

“…In light of the importance for phosphatase inhibition, of acidic functionality on the threonyl residue, these results can be rationalized in terms of poor cell penetration of stevastelin A, as contrasted to good penetration of inactive stevastelin B, followed by intracellular conversion of stevastelin B to an active inhibitory form by sulfation or phosphorylation on the threonyl hydroxyl. 140 Another natural product, the Streptomycese-derived butyrolactone, RK-682 (6), also exhibits potent noncompetitive inhibition of VHR, with an IC 50 value of 2.0 M. 141,142 Several natural product derived inhibitors have been discovered that are active against the cdc25 family of dual specificity phosphatases. Among these are the sesterpene ␥-hydroxybutenolide, dysidiolide (7), isolated from the marine sponge Dysidea etheria de Laubenfels, (cdc25A, IC 50 ly.…”

Section: Natural Product-derived Inhibitorsmentioning

confidence: 99%

Protein-tyrosine phosphatases: Structure, mechanism, and inhibitor discovery

1998

View full text Add to dashboard Cite

Protein–tyrosine kinases (PTKs) and their associated signaling pathways are crucial for the regulation of numerous cell functions including growth, mitogenesis, motility, cell–cell interactions, metabolism, gene transcription, and the immune response. Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation states of proteins are governed by the opposing actions of PTKs and protein–tyrosine phosphatases (PTPs). In this light, both PTKs and PTPs play equally important roles in signal transduction in eukaryotic cells, and comprehension of mechanisms behind the reversible pTyr‐dependent modulation of protein function and cell physiology must necessarily encompass the characterization of PTPs as well as PTKs. In spite of the large number of PTPs identified to date and the emerging role played by PTPs in disease, a detailed understanding of the role played by PTPs in signaling pathways has been hampered by the absence of PTP‐specific agents. Such PTP‐specific inhibitors could potentially serve as useful tools in determining the physiological significance of protein tyrosine phosphorylation in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. The goal of this review is therefore to summarize current understandings of PTP structure and mechanism of catalysis and the relationship of these to PTP inhibitor development. The review is organized such that enzyme structure is covered first, followed by mechanisms of catalysis then PTP inhibitor development. In discussing PTP inhibitor development, nonspecific inhibitors and those obtained by screening methods are initially presented with the focus then shifting to inhibitors that utilize a more structure‐based rationale. © 1998 John Wiley & Sons, Inc. Biopoly 47: 225–241, 1998

show abstract

Stevastelins, a novel group of immunosuppressants, inhibit dual-specificity protein phosphatases

Cited by 40 publications

References 28 publications

TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

Regulation of Vaccinia H1-related (VHR) Phosphatase Activity by NSC-87877

Protein-tyrosine phosphatases: Structure, mechanism, and inhibitor discovery

Contact Info

Product

Resources

About