Rerouting of fibroblast growth factor 2 to the classical secretory pathway results in post-translational modifications that block binding to heparan sulfate proteoglycans.
FGF-2 is a proangiogenic growth factor secreted by unconventional means. It is unknown why FGF-2 takes an ER/Golgi-independent secretory route. We find that secretion of FGF-2 via the ER/Golgi system causes post-translational modifications that prevent binding to heparan sulfate proteoglycans (HSPGs), an interaction that is critically important for both FGF-2 storage and signal transduction. This loss of function is due to artificial O-glycosylation mainly resulting in the addition of glycosaminoglycan chains of the chrondroitin sulfate type. Our findings suggest that the unconventional mechanism of FGF-2 export is an ancient pathway of protein secretion that, in the course of evolution, has been kept due to the inability of the classical secretory pathway to export FGF-2 in a functional form.
Wegehingel
Sabine
S
Heidelberg University, Biochemistry Center, Germany.
Zehe
Christoph
C
Nickel
Walter
W
D000818:Animals; D016466:CHO Cells; D002809:Chondroitin Sulfates / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals
D019812:Heparan Sulfate Proteoglycans; D021382:Protein Sorting Signals; C038142:chondroitin sulfate glycosaminoglycan; D016222:Fibroblast Growth Factor 2; D006493:Heparin; D002809:Chondroitin Sulfates