MUTANTS OF BASIC FIBROBLAST GROWTH-FACTOR IDENTIFY DIFFERENT CELLULAR-RESPONSE PROGRAMS

Mutations, expected to affect the intracellular routing, i.e. addition al nuclear localization sequences (NLS; the natural 23 kDa isoform and a 17D27R mutant) and/or a deletion of amino acids 26-29 (23 Delta 26- 29 and 17 Delta 26-29), were introduced in basic fibroblast growth fac tor (bFGF), The mutants were assayed for their mitotic activity and th eir capacity to induce a tissue-specific response in human umbilical v ein endothelial cells [HUVECs; induction of urokinase plasminogen acti vator receptor (u-PAR)], or in rat lens epithelial cells (fibre cell d ifferentiation). In HUVECs, the 17D27R mutant had wild type activity, the 23 kDa and the Delta 26-29 proteins were impaired in the induction of both mitosis and u-PAR, The Delta 26-29 proteins, but not the 23 k Da protein or 17D27R mutant, were also-impaired in receptor binding in that they bound only to a subset of receptors. The concentration of 1 7 kDa bFGF required for half maximal u-PAR response was 30 fold higher than for the half maximal H-3-thymidine incorporation. Addition of an NLS to bFGF strongly inhibited the induction of fibre cell differenti ation, though it had little effect on the stimulation of DNA synthesis , The 17 Delta 26-29 kDa mutant had wild type differentiation activity but was a poor mitogen for lens epithelial cells.