Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P-2)-dependent Oligomerization of 
Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane 
Pore Implicated in Unconventional Secretion

Steringer, J. P.; Bleicken, S.; Andreas, H.; Zacherl, S.; Laussmann, M.; Temmerman, K.; Contreras, F. X.; Bharat, T. A. M.; Lechner, J.; Muller, H. M.; Briggs, John A. G.; Garcia-Saez, A. J.; Nickel, W.

doi:10.1074/jbc.M112.381939

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Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P-2)-dependent Oligomerization of Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane Pore Implicated in Unconventional Secretion

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Citation

Steringer, J. P., Bleicken, S., Andreas, H., Zacherl, S., Laussmann, M., Temmerman, K., et al. (2012). Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P-2)-dependent Oligomerization of Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane Pore Implicated in Unconventional Secretion. Journal of Biological Chemistry, 287(33), 27659-27669. doi:10.1074/jbc.M112.381939.

Cite as: https://hdl.handle.net/21.11116/0000-0009-70FC-D

Abstract

Fibroblast growth factor 2 (FGF2) is a critical mitogen with a central role in specific steps of tumor-induced angiogenesis. It is known to be secreted by unconventional means bypassing the endoplasmic reticulum/Golgi-dependent secretory pathway. However, the mechanism of FGF2 membrane translocation into the extracellular space has remained elusive. Here, we show that phosphatidylinositol 4,5-bisphosphate-dependent membrane recruitment causes FGF2 to oligomerize, which in turn triggers the formation of a lipidic membrane pore with a putative toroidal structure. This process is strongly up-regulated by tyrosine phosphorylation of FGF2. Our findings explain key requirements of FGF2 secretion from living cells and suggest a novel self-sustained mechanism of protein translocation across membranes with a lipidic membrane pore being a transient translocation intermediate.