Nuclear signaling pathways for polypeptide ligands and their membrane receptors?

Classical signal transduction theory revolves around the premise that the role of membrane receptors is to transfer the signal represented by ligand binding from the external cell surface across the membrane to within the cell. Other components of the signaling cascade such as second-messenger molecules and kinases then convey the signal from the cytoplasm to the nucleus to effect changes in gene expression. Membrane receptor endocytosis is seen as part of the cellular down-regulation and desensitization apparatus rather than as having an active signaling function. Evidence is mounting, however, that polypeptide ligands and their membrane receptors may have an important additional signaling role within the cell including the nucleus. Several ligands such as those of the platelet-derived and fibroblast growth factor classes have been found not only to localize in the nucleus, but also to possess sequences similar to the nuclear localization signal of the simian virus SV40 large T antigen. In most cases where they have been examined, these sequences appear to be both functional in nuclear targeting and essential for full signaling activity. The implication is that subsequent to internalization, polypeptide ligands and/or their receptors may translocate to the nucleus and participate directly in regulating gene expression.