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A Functional Nuclear Localization Signal in Insulin-Like Growth Factor Binding Protein-6 Mediates Its Nuclear Import

Departments of Biochemistry and Pediatrics (C.I., T.G., C.Y.H.J., S.S.-C.L., V.K.M.H.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1; and Children’s Health Research Institute and Lawson Health Research Institute (C.I., S.S.-C.L., V.K.M.H.), London, Ontario, Canada N6C 2V5

Address all correspondence and requests for reprints to: Victor Han, M.D., Children’s Health Research Institute, A5-107 Victoria Research Laboratories, 800 Commissioner’s Road East, London, Ontario, Canada N6C 2V5. E-mail: victor.han{at}sjhc.london.on.ca.

IGF binding protein (IGFBP)-6 is a member of the IGFBP family that regulates the actions of IGFs. Although IGFBPs exert their functions extracellularly in an autocrine/paracrine manner, several members of the family, such as IGFBP-3 and -5, possess nuclear localization signals (NLS). To date, no NLS has been described for IGFBP-6, an IGFBP that binds preferentially to IGF-II. We report here that both exogenous and endogenous IGFBP-6 could be imported into the nuclei of rhabdomyosarcoma and HEK-293 cells. Nuclear import of IGFBP-6 was mediated by a NLS sequence that bears limited homology to those found in IGFBP-3 and -5. IGFBP-6 nuclear translocation was an active process that required importins. A peptide corresponding to the IGFBP-6 NLS bound preferentially to importin-. A comprehensive peptide array study revealed that, in addition to positively charged residues such as Arg and Lys, amino acids, notably Gly and Pro, within the NLS, played an important part in binding to importins. Overexpression of wild-type IGFBP-6 increased apoptosis, and the addition of IGF-II did not negate this effect. Only the deletion of the NLS segment abolished the apoptosis effect. Taken together, these results suggest that IGFBP-6 is translocated to the nucleus with functional consequences and that different members of the IGFBP family have specific nuclear import mechanisms.

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