Working without kinase activity: phosphotransfer-independent functions of extracellular signal-regulated kinases.
The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) and ERK2 play well-characterized roles in the regulation of key cellular processes, such as proliferation, differentiation, and survival, by acting as serine and threonine kinases in the phosphorylation of ~200 substrates that are distributed in different subcellular localizations. However, over the past few years, evidence has mounted that indicates that the mechanism of action of ERK1 and ERK2 may extend beyond their role as canonical kinases. For example, proteins such as poly(ADP-ribose) polymerase 1, topoisomerase II, and MAPK phosphatase 3 (MKP-3) are activated by a direct interaction with ERK2 that does not involve any phosphotransfer activity. In addition, ERK2 binds to DNA and acts as a transcriptional regulator independently of its function as a kinase. Moreover, other studies demonstrate that ERK1 and ERK2 can regulate cell cycle entry by disrupting the interaction between the retinoblastoma pocket protein and lamin A in a kinase-independent fashion. These findings strongly support the notion that ERK1 and ERK2 can play functionally important roles independently of their regular catalytic activities and provide the basis for a new perspective from which to view these hitherto archetypical signaling kinases.
Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina. Santander, 39011, Cantabria, Spain.
Javier
J
Rodríguez
Piero
P
Crespo
D003599:Cytoskeleton / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding
C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6