The Ras/ERK MAP kinase signaling cascade is activated by many extracellular stimuli and is critical to a variety of cellular processes. The molecules that make up this cascade are present in different subcellular compartments and exactly where the cascade is activated depends on the extracellular stimulus. ERK activity can influence molecules in the cell cytoplasm or it can influence whether target genes in the nucleus are turned on or off. It is not known exactly how a particular stimulus can confine Ras/ERK MAP activity to a specific region of the cell.
A molecule called hSef was recently identified as an inhibitor of this cascade but the molecular mechanisms of inhibition are unclear. Dr. Eisuke Nishida from The Department of Cell and Developmental Biology at Kyoto University in Japan examined exactly how hSef influences Ras/ERK MAP kinase signaling in the cytoplasm and nucleus. When cells were stimulated with a common growth factor, hSef interacted with activated ERK in the cytoplasm. The inhibitor was only switched on when the Ras/ERK MAP kinase pathway was activated. Interestingly, activated hSef works not by directly inhibiting the activity of ERK, but by preventing activated ERK from entering the nucleus. When hSef levels were experimentally reduced, stimulus-dependant ERK activation in the nucleus increased dramatically.
These results demonstrate that the newly discovered inhibitor hSef is a signaling-dependent regulator of the Ras/ERK MAP kinase cascade that blocks MAP kinase influence on target genes by restricting where ERK activity is localized within the cell. The authors suggest that the next step will be to determine what regulates hSef production and function.
Satoru Torii, Morioh Kusakabe, Takuya Yamamoto, Momoko Maekawa, and Eisuke Nishida: "Sef Is a Spatial Regulator for Ras/MAP Kinase Signaling"
Publishing in Developmental Cell, Volume 7, Number 1, July 2004, pages 33-44.
Journal
Developmental Cell