A carboxyl-terminal domain in fibroblast growth factor (FGF)-2 inhibits FGF-1 release in response to heat shock in vitro.

The fibroblast growth factor (FGF) prototypes, FGF-1 and FGF-2, lack a signal sequence, but both contain a nuclear localization sequence. We prepared a series of FGF-1 deletion mutants fused to the reporter gene, beta-galactosidase (beta-gal) and determined that a domain between residues 83 and 154 is responsible for FGF-1 cytosol retention in NIH 3T3 cells. Using a series of FGF-beta-gal chimeric proteins prepared by the shuffling of cassette-formatted synthetic FGF prototype genes, we were able to demonstrate that the nuclear localization sequence from the 5'-CUG region of FGF-2 is not able to direct the nuclear association of FGF-1 due to its inability to repress the function of the FGF-1 cytosol retention domain. We also observed that while the FGF-1:beta-gal chimera was released in response to heat shock, the FGF-2:beta-gal protein was not. Further, replacement of the FGF-1 cytosol retention domain with the corresponding domain from FGF-2 repressed the release of the chimeric protein. These data suggest that the specificity of the stress-induced secretion pathway for FGF-1 involves a carboxyl-terminal domain that is absent in FGF-2 and that the FGF-1 secretion pathway does not restrict the release of high molecular weight forms of FGF-1.