Secreted cysteine-rich FGF receptor derives from posttranslational processing by furin-like prohormone convertases.
Cysteine-rich FGF receptor (CFR) was originally identified as a FGF2 receptor and found to be identical to Golgi complex-localized glycoprotein-1 (GLG1), also known as MG-160, and to a murine E-selectin ligand-1 (ESL-1). Although CFR is a 150-kDa integral membrane glycoprotein that is primarily located in the cis-medial Golgi complex, a substantial proportion of CFR is secreted but the underlying mechanism is unknown. CFR contains several possible furin-like proprotein convertase (PC) and matrix metalloproteinase cleavage sites. Cells expressing CFR were treated with the furin protease inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decCMK) or the MMP-inhibitor GM6001. In the presence of furin-like PC inhibitor, secretion of CFR was almost completely inhibited. Secretion was not affected by the GM6001 inhibitor. The secreted forms were further characterized by creating different mutant CFR proteins with N-terminal and C-terminal tags. Immunoblot analysis and immunofluorescence indicated, that successive endoproteolytical processing of CFR which takes place in the Golgi complex is essential for secretion. Secreted CFR bound to heparan sulphate proteoglycan (HSPG) could trap FGFs and thereby directly competing with tyrosine kinase receptors for FGF binding.
Antoine
Marianne
M
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
Köhl
Roman
R
Tag
Carmen G
CG
Gressner
Axel M
AM
Hellerbrand
Claus
C
Kiefer
Paul
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002645:Chickens; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009154:Mutation; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C086711:cysteine-rich fibroblast growth factor receptor; C460143:decanoylRVKRchloromethylketone; D005346:Fibroblast Growth Factors; D043484:Proprotein Convertases; D045683:Furin; D008666:Metalloendopeptidases