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Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR.
Tautz, lutz; Mustelin, Tomas; Wu, Shuangding et al.
2009
 

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Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Tautz, lutz
Mustelin, Tomas
Wu, Shuangding
Vossius, Sofie
Rahmouni, Souad  ;  Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.
Vasile, Stefan
Sergienko, Eduard
Stonich, Derek
Yuan, Hongbin
Su, Hongbin
Dahl, Ying
Mostofi, Yalda
Chung, Thomas DY
More authors (3 more) Less
Language :
English
Title :
Small-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR.
Publication date :
2009
Publisher :
National Center for Biotechnology Information (US), Bethesda, United States
Commissioned by :
NIH
Available on ORBi :
since 03 May 2011

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