FGF1 and
FGF2 bind to specific cell-surface
tyrosine kinase receptors (FGFRs) and activate intracellular signaling that leads to proliferation, migration or differentiation of many cell types. Besides this classical mode of action, under stress conditions,
FGF1 and
FGF2 are translocated in a receptor-dependent manner via the endosomal membrane into the cytosol and nucleus of the cell. However, despite many years of research, the role of translocated
FGF1 and
FGF2 inside the cell remains unclear. Here, we reveal an anti-apoptotic activity of intracellular
FGF1 and
FGF2, which is independent of FGFR activation and downstream signaling. We observed an inhibition of cell apoptosis induced by serum
starvation or
staurosporine upon treatment with exogenous
FGF1 or
FGF2, despite the presence of highly potent FGFR inhibitors. Similar results were found when the
tyrosine kinase of FGFR1 was completely blocked by a specific mutation. Moreover, the anti-apoptotic effect of the
growth factors was abolished by known inhibitors of the translocation of
FGF1 and
FGF2 from the endosomes to the interior of the cell. Interestingly,
FGF2 showed higher anti-apoptotic activity than
FGF1. Since
FGF2 is not phosphorylated by PKCĪ“ and is present inside the nucleus longer than is
FGF1, we speculated that the different activities could reflect their diverse nuclear export kinetics. Indeed, we observed that
FGF1 mutations preventing binding to
nucleolin and therefore phosphorylation in the nucleus affect the anti-apoptotic activity of
FGF1. Taken together, our data indicate that the translocation of
FGF1 and
FGF2 protects cells against apoptosis and promotes cell survival.