Dual localization: proteins in extracellular and intracellular compartments

The goal of this article is to provide a comprehensive catalog of those proteins documented to exhibit dual localization, being found in both the extracellular compartment (cell surface and extracellular medium) as well as the intracellular compartment (cytosol and nucleus). A large subset of these proteins that show dual localization is found both in the nucleus and outside of cells. Proteins destined to be secreted out of the cell or to be expressed at the cell surface usually enter the endomembrane pathway on the basis of a signal sequence that targets them into the endoplasmic reticulum. Proteins destined for import into the nucleus, on the other hand, usually carry a nuclear localization signal. We have organized our catalog in terms of the presence and absence of these trafficking signals: (a) proteins that contain a signal sequence but no nuclear localization signal; (b) proteins that contain both a signal sequence as well as a nuclear localization signal; (c) proteins that contain a nuclear localization signal but lack a signal sequence; and (d) proteins containing neither a signal sequence nor a nuclear localization signal. Novel insights regarding the activities of several classes of proteins exhibiting dual localization can be derived when one targeting signal is experimentally abrogated. For example, the mitogenic activity of both fibroblasts growth factor-1 and schwannoma-derived growth factor clearly requires nuclear localization, independent of the activation of the receptor tyrosine kinase signaling pathway. In addition, there is a growing list of integral membrane receptors that undergo translocation to the nucleus, with bona fide nuclear localization signals and transcription activation activity. The information provided in this descriptive catalog will, hopefully, stimulate investigations into the pathways and mechanisms of transport between these compartments and the physiological significance of dual localization.