Diverse physiological functions for dual-specificity MAP kinase phosphatases.
A structurally distinct subfamily of ten dual-specificity (Thr/Tyr) protein phosphatases is responsible for the regulated dephosphorylation and inactivation of mitogen-activated protein kinase (MAPK) family members in mammals. These MAPK phosphatases (MKPs) interact specifically with their substrates through a modular kinase-interaction motif (KIM) located within the N-terminal non-catalytic domain of the protein. In addition, MAPK binding is often accompanied by enzymatic activation of the C-terminal catalytic domain, thus ensuring specificity of action. Despite our knowledge of the biochemical and structural basis for the catalytic mechanism of the MKPs, we know much less about their regulation and physiological functions in mammalian cells and tissues. However, recent studies employing a range of model systems have begun to reveal essential non-redundant roles for the MKPs in determining the outcome of MAPK signalling in a variety of physiological contexts. These include development, immune system function, metabolic homeostasis and the regulation of cellular stress responses. Interestingly, these functions may reflect both restricted subcellular MKP activity and changes in the levels of signalling through multiple MAPK pathways.
Dickinson
Robin J
RJ
Cancer Research UK Stress Response Laboratory, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Keyse
Stephen M
SM
D000818:Animals; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000502:physiology*; D054638:Dual Specificity Phosphatase 1; D047108:Embryonic Development; D017874:Immediate-Early Proteins / Q000502:physiology*; D007109:Immunity; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D010920:Placenta / Q000502:physiology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000276:immunology
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases