Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation
| Autor: | Xochella Chan, Eduard Sergienko, David A Critton, Ekaterina V. Bobkova, Nicholas D. P. Cosford, Li Yang, Rebecca Page, Paul J. Lombroso, Brock Brown, Shyama Sidique, Justin Rascon, Stefan Vasile, Ying Su, Thomas D.Y. Chung, Russell Dahl, Tomas Mustelin, Hongbin Yuan, Sharon Colayco, Wallace Liu, Lutz Tautz, Jian Xu |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Cell signaling Cell cycle checkpoint T-Lymphocytes p38 mitogen-activated protein kinases T cell Phosphatase Protein tyrosine phosphatase Biology p38 Mitogen-Activated Protein Kinases Biochemistry Article Cell Line Mice Structure-Activity Relationship Genetics medicine Animals Humans Enzyme Inhibitors Molecular Biology Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Chemistry Kinase Hematopoietic Protein Tyrosine Phosphatase General Medicine Molecular biology Cell biology Enzyme Activation Mice Inbred C57BL medicine.anatomical_structure Cancer cell Molecular Medicine Protein Tyrosine Phosphatases Biotechnology |
| Zdroj: | ACS Chemical Biology. 7:367-377 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb2004274 |
| Popis: | The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of blood cancers through its ability to negatively regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Small-molecule modulators of HePTP activity may become valuable in treating hematopoietic malignancies such as T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such compounds will further elucidate the regulation of MAPKs in hematopoietic cells. Although transient activation of MAPKs is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, cell senescence, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. Here, we report the development of a small molecule that augments ERK1/2 and p38 activation in human T cells, specifically by inhibiting HePTP. Structure-activity relationship analysis, in silico docking studies, and mutagenesis experiments reveal how the inhibitor achieves selectivity for HePTP over related phosphatases by interacting with unique amino acid residues in the periphery of the highly conserved catalytic pocket. Importantly, we utilize this compound to show that pharmacological inhibition of HePTP not only augments, but also prolongs activation of ERK1/2 and, especially, p38. Moreover, we present similar effects in leukocytes from mice intraperitoneally injected with the inhibitor at doses as low as 3 mg/kg. Our results warrant future studies with this probe compound that may establish HePTP as a new drug target for acute leukemic conditions. |
| Databáze: | OpenAIRE |
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