MAPK-specific tyrosine phosphatases: new targets for drug discovery?
Protein tyrosine phosphatases (PTPs) have key roles in a diverse range of cellular processes, and their dysregulation is associated with several human diseases. Many PTPs are recognized as potential drug targets; however, inhibitor development has focused only on a small number of enzymes, most notably PTP1B for type II diabetes and obesity, and MKP1 and CDC25 for cancer. The future challenge of selective-inhibitor development for PTPs will be significantly facilitated by the recent rapid progress in the structural biology of the 'PTPome'. In this article, we focus on the family of mitogen-activated protein kinase (MAPK)-specific tyrosine phosphatases--PTPN5 [also called striatal-enriched phosphatase (STEP)], PTPN7 (also called hematopoietic PTP) and PTPRR (also called PC12 PTP or STEP-like PTP)--and discuss approaches for achieving selectivity for the MAPK-PTPs at the molecular level using recently determined high-resolution X-ray crystal structures. We believe that the development of specific inhibitors would provide a valuable set of experimental pharmacological tools for investigating the physiological role of these phosphatases and exploring their emerging role in human disease.
Barr
Alastair J
AJ
Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford, OX3 7LD, UK. alastair.barr@sgc.ox.ac.uk
Knapp
Stefan
S
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D008958:Models, Molecular; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology
D020929:Mitogen-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases