Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P2)-dependent Oligomerization of Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane Pore Implicated in Unconventional Secretion

• Published in: The Journal of biological chemistry 2012-08, Vol.287 (33), p.27659-27669
• Main Authors: Steringer, Julia P., Bleicken, Stephanie, Andreas, Helena, Zacherl, Sonja, Laussmann, Mareike, Temmerman, Koen, Contreras, F. Xabier, Bharat, Tanmay A.M., Lechner, Johannes, Müller, Hans-Michael, Briggs, John A.G., García-Sáez, Ana J., Nickel, Walter
• Format: Article
• Language: English
• Subjects: Cell Membrane - chemistry; Cell Membrane - genetics; Cell Membrane - metabolism; Fibroblast Growth Factor 2; Fibroblast Growth Factor 2 - chemistry; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Humans; Lipid-binding Protein; Membrane Biology; Membrane Lipids; Membrane Reconstitution; Membrane Structure; Phosphatidylinositol 4,5-Diphosphate - chemistry; Phosphatidylinositol 4,5-Diphosphate - genetics; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphoinositides; Phosphorylation - physiology; Protein Multimerization - physiology; Protein Translocation across Membranes; Protein Transport - physiology; Transport; Tyrosine Phosphorylation; Unconventional Secretion
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.381939

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. Background: PI(4,5)P2- and tyrosine phosphorylation-dependent unconventional secretion of FGF2 is mediated by direct translocation across the plasma membrane. Results: PI(4,5)P2-mediated membrane recruitment causes oligomerization of tyrosine-phosphorylated FGF2 that, in turn, triggers the formation of a lipidic membrane pore. Conclusion: Membrane-inserted FGF2 oligomers represent intermediates of membrane translocation during unconventional secretion. Significance: Mechanistic insight into a novel self-sustained mechanism of protein translocation across membranes is provided.