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Vol. 15, Issue 2, 801-814, February 2004

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Translocation of FGF-1 and FGF-2 across Vesicular Membranes Occurs during G₁-Phase by a Common Mechanism

Jedrzej Maecki, Jørgen Wesche, Camilla Skiple Skjerpen, Antoni Wiedocha, and Sjur Olsnes ^*

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

Submitted August 13, 2003; Revised October 3, 2003; Accepted October 21, 2003
Monitoring Editor: Keith Mostov

The entry of exogenous fibroblast growth factor 2 (FGF-2) to the cytosolic/nuclear compartment was studied and compared with the translocation mechanism used by FGF-1. To differentiate between external and endogenous growth factor, we used FGF-2 modified to contain a farnesylation signal, a CaaX-box. Because farnesylation occurs only in the cytosol and nucleoplasm, farnesylation of exogenous FGF-2-CaaX was taken as evidence that the growth factor had translocated across cellular membranes. We found that FGF-2 translocation occurred in endothelial cells and fibroblasts, which express FGF receptors, and that the efficiency of translocation was increased in the presence of heparin. Concomitantly with translocation, the 18-kDa FGF-2 was N-terminally cleaved to yield a 16-kDa form. Translocation of FGF-2 required PI3-kinase activity but not transport through the Golgi apparatus. Inhibition of endosomal acidification did not prevent translocation, whereas dissipation of the vesicular membrane potential completely blocked it. The data indicate that translocation occurs from intracellular vesicles containing proton pumps and that an electrical potential across the vesicle membrane is required. Translocation of both FGF-1 and FGF-2 occurred during most of G₁ but decreased shortly before the G₁S transition. A common mechanism for FGF-1 and FGF-2 translocation into cells is postulated.

Abbreviations used: FGF, fibroblast growth factor; MAP-kinase, mitogen-activated protein kinase; TCA, trichloroacetic acid.

^* Corresponding author. E-mail address: olsnes{at}radium.uio.no.

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