References of "Sergienko, Eduard"
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See detailDUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia ULg; Kuijpers, Marijke; Gilio, Karen et al

in Circulation (in press)

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet ... [more ▼]

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. [less ▲]

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See detailSmall-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR.
Tautz, lutz; Mustelin, Tomas; Wu, Shuangding et al

Report (2009)

Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated ... [more ▼]

Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated protein (MAP) kinases mediate major signaling pathways triggered by extracellular growth factor, stress, or cytokines and regulate cellular processes such as differentiation, proliferation and apoptosis. Unlike many MAP kinase phosphatases (MKPs), VHR expression is not induced in response to activation of MAP kinases, but is instead regulated during cell cycle progression. The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1. This novel small molecular probe, ML113 (CID-6161281) appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. As a result, it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism underlying the selectivity against this phosphatase, in addition to providing greater understanding of the functional consequences for cancer biology. [less ▲]

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