INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN (IGFBP)-3 AND IGFBP-5 SHARE A COMMON NUCLEAR TRANSPORT PATHWAY IN T47D HUMAN BREAST-CARCINOMA CELLS

Insulin-like growth factor-binding proteins (IGFBPs) play an integral role in modifying insulin-like growth factor actions in a wide variety of cell types. Recent evidence suggests that IGFBP-3 and IGFBP-5 also have effects on cell growth that are insulin-like growth factor-indep endent. In investigating possible mechanisms for this effect, the intr acellular trafficking of IGFBP-3 and IGFBP-5, both of which contain se quences with the potential for nuclear localization, was studied in T4 7D cells. Nuclear uptake of fluorescently labeled IGFBP-3 and IGFBP-5 was observed in a proportion of T47D cells that appeared to be rapidly dividing. IGFBP-1 and IGFBP-2, which do not possess the putative doma in for nuclear translocation, were not transported to the nuclei of T4 7D cells. When T47D cells were preincubated with excess unlabeled IGFB P-3, nuclear localization of labeled IGFBP-3 or IGFBP-5 was not detect ed, indicating that their nuclear translocation involves a common path way, Inhibition of receptor-mediated endocytosis did not affect nuclea r uptake of IGFBP-3, suggesting that it uses an alternative non-classi cal import pathway for transport across the plasma membrane. In additi on, a variant form of IGFBP-3 with a mutation in the putative nuclear localization sequence was unable to translocate to the nuclei of T47D cells, suggesting that nuclear translocation of IGFBP-3 was dependent on these carboxyl-terminal basic residues.