Uncoupling of cell proliferation and differentiation activities of basic fibroblast growth factor.
FGF-2 exerts its pleiotropic effects on cell growth and differentiation by interacting with specific cell surface receptors. In addition, exogenously added FGF-2 is translocated from outside the cell to the nucleus during G1-S transition. In this study, we show that a single point mutation in FGF-2 (substitution of residue serine 117 by alanine) is sufficient to drastically reduce its mitogenic activity without affecting its differentiation properties. The FGF-2(S117A) mutant binds to and activates tyrosine kinase receptors and induces MAPK and p70S6K activation as strongly as the wild-type FGF-2. We demonstrate that this mutant enters NIH3T3 cells, is translocated to the nucleus, and is phosphorylated similar to the wild-type growth factor. This suggests that FGF-2 mitogenic activity may require, in addition to signaling through cell surface receptors and nuclear translocation, activation of nuclear targets. We have previously shown that, in vitro, FGF-2 directly stimulates the activity of the casein kinase 2 (CK2), a ubiquitous serine/threonine kinase involved in the control of cell proliferation. We report that, in vivo, FGF-2(WT) transiently interacts with CK2 and stimulates its activity in the nucleus during G1-S transition in NIH3T3 cells. In contrast, the FGF-2(S117A) mutant fails to interact with CK2. Thus, our results show that FGF-2 mitogenic and differentiation activities can be dissociated by a single point mutation and that CK2 may be a new nuclear effector involved in FGF-2 mitogenic activity.-Bailly, K., Soulet, F., Leroy, D., Amalric, F., Bouche, G. Uncoupling of cell proliferation and differentiation activities of basic fibroblast growth factor (FGF-2).
Bailly
K
K
Institut de Pharmacologie et de Biologie Structurale du CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France.
Soulet
F
F
Leroy
D
D
Amalric
F
F
Bouche
G
G
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D047390:Casein Kinase II; D002417:Cattle; D002451:Cell Compartmentation; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000235:genetics / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction
D008934:Mitogens; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases