Nuclear trafficking of secreted factors and cell-surface receptors: new pathways to regulate cell proliferation and differentiation, and involvement in cancers

Nuclear secreted proteins and transmembrane receptors now appear to induce new signaling pathways to regulate cell proliferation and differentiation. Their nuclear localization is often transient, appearing only during certain phases of the cell cycle. Nuclear secreted and transmembrane molecules regulate the proliferation and differentiation of a large panel of cell types during embryogenesis and adulthood and are also potentially involved in wound healing. Secreted factors such as CCN proteins, EGF, FGFs and their receptors are often detected in the nucleus of cancer cells. Nuclear localization of these molecules has been correlated with tumor progression and poor prognosis for patient survival. Nuclear growth factors and receptors may be responsible for resistance to radiotherapy.The classical view of the way secreted molecules such as growth factors and protein hormones operated was that they acted at the cell surface by binding membrane receptors and activating cascades of intracellular second messengers, leading to the regulation of expression of specific target genes. Their internalization in endosomal vesicles and degradation in lysosomal compartment was seen as a way to stop their activation (For further details, see review [1]). But some evidence showed that their modes of action seem to be more complex. An unexpected finding was that internalized Fibroblast Growth Factors (FGFs) can have a long life inside the cell (over 24 hours), and it has been shown that several FGFs such as FGF1, FGF2 and FGF3 can act both extracellularly and intracellularly.Nuclear localization of FGFs and Epidermal Growth Factor (EGF) and of their cell surface receptors (FGFRs and EGFR respectively) has been well documented over the last 15 years in normal and physiopathological states. The deciphering of the underlying mechanisms of such apparently unexpected subcellular localization revealed that secreted factors and their receptors were internalized into the cytoplasm and routed