An alternatively spliced fibroblast growth factor (FGF)-5 mRNA is abundant in brain and translates into a partial agonist/antagonist for FGF-5 neurotrophic activity.
We detected in the brain and then cloned two novel, short forms of human and mouse fibroblast growth factor (FGF)-5 mRNA, which were designated human FGF-5S (hFGF-5S) and mouse FGF-5S (mFGF-5S), respectively. Genomic analysis indicated that mFGF-5S and authentic mFGF-5 mRNAs were transcribed from a single gene; hFGF-5S and mFGF-5S mRNAs were generated by excluding the second exon of the respective FGF-5 genes, and the alternatively spliced mRNAs encoded for 123- and 121-amino acid proteins, respectively. Indeed, a neuron-like cell line expressing mFGF-5S mRNA secreted a protein of the expected size and with FGF-5 antigenicity. In PC12 cells, expression of hFGF-5 or exposure to hFGF-5 protein induced differentiation. Neither expression of hFGF-5S, alone, nor co-expression of hFGF-5S with hFGF-5 induced significant differentiation. At high concentrations, hFGF-5S protein partially antagonized FGF-5 activity, whereas by itself, hFGF-5S exerted very weak neurotrophic activity. hFGF-5S protein binds to FGF receptor (FGFR)-1 on PC12 transfectants and partially inhibits hFGF-5-induced tyrosine phosphorylation of FGFR-1 and an FGFR substrate, but it also induces phosphorylation by itself. These results suggest that FGF-5S is a naturally expressed partial agonist/antagonist of FGF-5 neurotrophic activity in the brain and that its effects are exerted in part at the level of the receptor.
Ozawa
K
K
Biosignaling Department, National Institute of Bioscience and Human Technology, Tsukuba, Ibaraki 305-8566, Japan.
Suzuki
S
S
Asada
M
M
Tomooka
Y
Y
Li
A J
AJ
Yoneda
A
A
Komi
A
A
Imamura
T
T
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004926:Escherichia coli / Q000235:genetics; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016716:PC12 Cells; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D012260:Ribonucleases / Q000378:metabolism
D018076:DNA, Complementary; C496449:FGF5 protein, human; C496450:Fgf5 protein, mouse; C496451:Fgf5 protein, rat; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors; D012260:Ribonucleases