A New Way in

Many cellular stimuli induce signaling cascades that terminate with a protein entering the nucleus to activate transcription of target genes. Most of these proteins contain a conserved stretch of amino acids known as a nuclear localization signal (NLS), which binds to the nuclear import factor importin alpha, and the complex translocates into the nucleus through the nuclear pores. However, the absence of an NLS in some signaling proteins suggested that they access the nucleus via alternative mechanisms. Now, Chuderland et al. find a new signal in the extracellular signal-related kinase 2 (ERK-2). A three-amino acid domain is phosphorylated upon stimulation, allowing the protein to bind to a different nuclear import factor, importin7, and enter the nucleus. A similar domain was found in other cytonuclear shuttling proteins, and the same phosphorylation-dependent mechanism was shown to occur for nuclear accumulation of SMAD3 and MEK1. Thus, this domain acts as a general nuclear translocation signal and represents a new mechanism whereby proteins can enter the nucleus. — HP*