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.
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.
Heidelberg University Biochemistry Center, 69120 Heidelberg, Germany.
Julia P
JP
Steringer
Stephanie
S
Bleicken
Helena
H
Andreas
Sonja
S
Zacherl
Mareike
M
Laussmann
Koen
K
Temmerman
F Xabier
FX
Contreras
Tanmay A M
TA
Bharat
Johannes
J
Lechner
Hans-Michael
HM
Müller
John A G
JA
Briggs
Ana J
AJ
García-Sáez
Walter
W
Nickel
D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology
D019269:Phosphatidylinositol 4,5-Diphosphate; D016222:Fibroblast Growth Factor 2