Tec-kinase-mediated phosphorylation of fibroblast growth factor 2 is essential for unconventional secretion.
Fibroblast growth factor 2 (FGF2) is a potent mitogen that is exported from cells by an endoplasmic reticulum (ER)/Golgi-independent mechanism. Unconventional secretion of FGF2 occurs by direct translocation across plasma membranes, a process that depends on the phosphoinositide phosphatidylinositol 4,5-biphosphate (PI(4,5)P(2)) at the inner leaflet as well as heparan sulfate proteoglycans at the outer leaflet of plasma membranes; however, additional core and regulatory components of the FGF2 export machinery have remained elusive. Here, using a highly effective RNAi screening approach, we discovered Tec kinase as a novel factor involved in unconventional secretion of FGF2. Tec kinase does not affect FGF2 secretion by an indirect mechanism, but rather forms a heterodimeric complex with FGF2 resulting in phosphorylation of FGF2 at tyrosine 82, a post-translational modification shown to be essential for FGF2 membrane translocation to cell surfaces. Our findings suggest a crucial role for Tec kinase in regulating FGF2 secretion under various physiological conditions and, therefore, provide a new perspective for the development of a novel class of antiangiogenic drugs targeting the formation of the FGF2/Tec complex.
Ebert
Antje D
AD
Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Laussmann
Mareike
M
Wegehingel
Sabine
S
Kaderali
Lars
L
Erfle
Holger
H
Reichert
Jürgen
J
Lechner
Johannes
J
Beer
Hans-Dietmar
HD
Pepperkok
Rainer
R
Nickel
Walter
W
D016475:3T3 Cells; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry; D034622:RNA Interference; D014443:Tyrosine / Q000737:chemistry
D019269:Phosphatidylinositol 4,5-Diphosphate; D011506:Proteins; D016222:Fibroblast Growth Factor 2; D014443:Tyrosine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases