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Vol. 16, Issue 2, 794-810, February 2005

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Phosphorylation-regulated Nucleocytoplasmic Trafficking of Internalized Fibroblast Growth Factor-1

Antoni Widocha ^*, Trine Nilsen, Jørgen Wesche, Vigdis Sørensen, Jdrzej Maecki, Ewa Marcinkowska, and Sjur Olsnes

Institute for Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway

Submitted May 12, 2004; Revised November 4, 2004; Accepted November 17, 2004
Monitoring Editor: Carl-Henrik Heldin

Fibroblast growth factor-1 (FGF-1), which stimulates cell growth, differentiation, and migration, is capable of crossing cellular membranes to reach the cytosol and the nucleus in cells containing specific FGF receptors. The cell entry process can be monitored by phosphorylation of the translocated FGF-1. We present evidence that phosphorylation of FGF-1 occurs in the nucleus by protein kinase C (PKC). The phosphorylated FGF-1 is subsequently exported to the cytosol. A mutant growth factor where serine at the phosphorylation site is exchanged with glutamic acid, to mimic phosphorylated FGF-1, is constitutively transported to the cytosol, whereas a mutant containing alanine at this site remains in the nucleus. The export can be blocked by leptomycin B, indicating active and receptor-mediated nuclear export of FGF-1. Thapsigargin, but not leptomycin B, prevents the appearance of active PKC in the nucleus, and FGF-1 is in this case phosphorylated in the cytosol. Leptomycin B increases the amount of phosphorylated FGF-1 in the cells by preventing dephosphorylation of the growth factor, which seems to occur more rapidly in the cytoplasm than in the nucleus. The nucleocytoplasmic trafficking of the phosphorylated growth factor is likely to play a role in the activity of internalized FGF-1.

^* Corresponding author. E-mail address: antoni.wiedlocha{at}labmed.uio.no.

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