Identification of novel nuclear localization signal within the ErbB-2 protein

ErbB2, a member of the receptor tyrosine kinase family, is frequently over-expressed in breast cancer. Proteolysis ofthe extracellular domain of ErbB2 results in constitutive activation of ErbB2 kinase. Recent study reported that ErbB2is found in the nucleus. Here, we showed that ErbB2 is imported into the nucleus through a nuclear localization signal(NLS)-mediated mechanism. The NLS sequence KRRQQKIRKYTMRR (aa655-668) contains three clusters of basicamino acids and it is sufficient to target GFP into the nucleus. However, mutation in any basic amino acid cluster of thisNLS sequence significantly affects its nuclear localization. Furthermore, it was found that this NLS is essential for thenuclear localization of ErbB2 since the intracellular domain of Erb2 lacking NLS completely abrogates its nucleartranslocation. Taken together, our study identified a novel nuclear localization signal and reveals a novel mechanismunderlying ErbB2 nuclear trafficking and localization.