Editors' ChoiceMAPK PATHWAY

Controlling ERK Signaling Location

Science's STKE  20 Jul 2004:
Vol. 2004, Issue 242, pp. tw261-TW261
DOI: 10.1126/stke.2422004TW261

Certain stimuli, such as growth factors, trigger the Ras-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway to elicit responses that affect processes such as cell growth and survival. Activated ERK can act on cytoplasmic targets, such as the serine-threonine kinase RSK, or it can translocate to the nucleus and phosphorylate substrates including the transcription factor Elk-1. A putative membrane protein called Sef (similar expression to fgf genes) inhibits the Ras-ERK signaling cascade in response to growth factors, but its point of action has not been clear. Torii et al. report that in response to growth factor stimulation, human Sef (hSef) binds to activated MEK within the MEK-ERK complex in the cytoplasm. Activated MEK phosphorylates, and hence activates, associated ERK, a modification that releases activated ERK to translocate to the nucleus. The study shows that in unstimulated cells, overexpressed hSef localized mainly to the Golgi apparatus. After stimulation with growth factor, some hSef translocated to the plasma membrane. Activated MEK and ERK colocalized with hSef at the Golgi and plasma membrane. Overexpression of hSef blocked growth factor-stimulated nuclear translocation of ERK, whereas knockdown of hSef expression by RNA interference increased ERK nuclear localization and expression of target genes in response to growth factor treatment. In growth factor-treated cells overexpressing both hSef and MEK, hSef was isolated in a complex with activated MEK. Although hSef inhibited phosphorylation of the nuclear target Elk-1, phosphorylation of the cytoplasmic target RSK was unaffected. The authors propose that hSef is a signaling-dependent regulator of the Ras-ERK pathway and restricts where ERK activation is localized within the cell.

S. Torii, M. Kusakabe, T. Yamamoto, M. Maekawa, E. Nishida, Sef is a spatial regulator for Ras/MAP kinase signaling. Devel. Cell 7, 33-44 (2004). [Online Journal]