Regulation of Nuclear Localization during Signaling

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Signaling pathways consist of a chain of biochemical events thatform the intracellular equivalent of a fire bucket brigade. An initialchange or chemical signal outside the cell is sensed at the cellsurface by a receptor, which then transduces the signal to thecytosol. Over the last few years, investigations have focused in-creasingly on the spatiotemporal aspects of signaling, and it hasbecome clear that the localization of key signaling components ishighly regulated during signal transduction. Most signal transduc-tion pathways cause specific changes in gene expression. Thus, anextracellular signal must be transduced across the plasma mem-brane and subsequently across the nuclear envelope to propagatethe signal from the cytosol to the nucleus. Many signaling re-sponses, therefore, rapidly effect the nuclear localization of tran-scription factors or alternatively of kinases that, once translocated,phosphorylate and activate transcription factors in the nucleus.Proteins travel into and out of the nucleus exclusively throughthe nuclear pore complex, an elaborate constellation of at least 30distinct components embedded in the nuclear envelope (1). Themechanism by which proteins travel through the nuclear pore isthe subject of much investigation (1); however in the past few yearsseveral aspects of nuclear transport have been clarified. Smallmolecules (less than 50,000 daltons) diffuse freely in and out of thenucleus through nuclear pores. To gain access to the nucleus,larger proteins require a nuclear localization sequence (NLS),