A GR-motif functions in nuclear accumulation of the large FGF-2 isoforms and interferes with mitogenic signalling.
Nuclear translocation has been documented for members of the fibroblast growth factor (FGF) family in addition to their roles as extra-cellular signalling molecules. Fusing different parts of the chicken FGF-2 open reading frame to pyruvate kinase shows that direct nuclear accumulation is mediated by the amino-termini of the two leucine initiated FGF-2 isoforms (Leu-isoforms; 21.5 and 20.0 kDa). An evolutionarily conserved glycine-arginine (GR)-motif is present in the 21.5 kDa Leu-isoform and a shorter GR-repeat in the 20.0 kDa Leu-isoform, whereas no such repeats are present in the 18.5 kDa FGF-2 isoform (Met-isoform). Expression in NIH3T3 fibroblasts shows that the 21.5 kDa Leu-isoform is predominantly nuclear, whereas the Met-isoform is predominantly cytoplasmic. Most importantly, insertion of the GR-motif into the Met-isoform results in a protein with characteristics similar to the Leu-isoforms, as shown by nuclear accumulation of the chimeric MGR-protein. Furthermore, only NIH3T3 fibroblasts expressing the Met-isoform proliferate under serum starvation conditions, whereas cells expressing either the MGR- or Leu-isoforms stay growth arrested. These studies show that the GR-signal mediates nuclear translocation of endogenous Leu-isoforms and blocks their mitogenic activity.
Dono
R
R
EMBL, Heidelberg, Germany.
James
D
D
Zeller
R
R
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002645:Chickens; D017124:Conserved Sequence; D016895:Culture Media, Serum-Free; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005998:Glycine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007536:Isomerism; D007930:Leucine; D008715:Methionine; D051379:Mice; D008934:Mitogens / Q000378:metabolism*; D008969:Molecular Sequence Data; D015398:Signal Transduction
D016895:Culture Media, Serum-Free; D008934:Mitogens; D016222:Fibroblast Growth Factor 2; D001120:Arginine; D008715:Methionine; D007930:Leucine; D005998:Glycine