Inhibition of FGF Receptor Function 
in Skin of Transgenic Animals 
Dr. Williams's group used slcin as a model system 
for inhibiting FGF function in a transgenic mouse by 
targeted expression of a dominant negative mutant 
FGF receptor that inhibits the function of wild-type 
FGF receptors. Using the keratin 10 promoter, they 
achieved localized expression of the mutant recep- 
tor in the suprabasal layer of the skin and thereby 
specifically blocked the action of FGF in this region. 
The suprabasal cells of these animals did not differ- 
entiate properly and proliferated excessively. Histo- 
logically the skin resembled that of patients with 
hyperproliferative skin diseases. These studies, 
which showed that FGF plays a role in promoting 
skin differentiation, were supported by a grant from 
the National Heart, Lung and Blood Institute, Na- 
tional Institutes of Health. 
Alternatively Spliced Forms 
of FGF Receptor Have Different 
Ligand Specificities 
Dr. Williams's group previously showed that the 
FGF receptor genes encode multiple receptors that 
differ in their extracellular domain sequences and 
are generated by alternative splicing. This year they 
found that each splice variant has a distinctive speci- 
ficity pattern in binding selected members of the 
FGF family of factors. They also showed that it is 
possible to inactivate selectively the response of an 
endogenous FGF receptor to a specific ligand in the 
FGF family by coexpressing a dominant negative 
mutant receptor that selectively binds that ligand. 
Dr. Williams is also Professor of Medicine at the 
University of California, San Francisco. 
Books and Chapters of Books 
Williams, L.T., Escobedo, J.A., Ueno, H., and Col- 
bert, H. 1991 . Signal transduction by the platelet- 
derived growth factor and fibroblast growth factor 
receptors. In Origins of Human Cancer: A Com- 
prehensive Review (Brugge, J., Curran, T., Har- 
low, E., and McCormick, F., Eds.). Plainview, NY: 
Cold Spring Harbor Laboratory, pp 237-245. 
Articles 
de Vries, C, Escobedo, J.A., Ueno, H., Houck, K., 
Ferrara, N., and Williams, L.T. 1992. The /m5- 
like tyrosine kinase, a receptor for vascular endo- 
thelial growth factor. Science 255:989-991. 
Duan, D.-S.R., Werner, S., and Williams, L.T. 1992. 
A naturally occurring secreted form of fibroblast 
growth factor (FGF) receptor 1 binds basic FGF in 
preference over acidic FGF. / Biol Chem 
267:16076-16080. 
Fantl, W.J., Escobedo, J.A., Martin, G.A., Turck, 
C.W., del Rosario, M., McCormick, F., and Wil- 
liams, L.T. 1992. Distinct phosphotyrosines on a 
growth factor receptor bind to specific molecules 
that mediate different signaling pathways. Cell 
69:413-423. 
Johnson, D.E., Lu,J., Chen, H., Werner, S., and Wil- 
liams, L.T. 1991. The human fibroblast growth 
factor receptor genes: a common structural ar- 
rangement underlies the mechanisms for generat- 
ing receptor forms that differ in their third immu- 
noglobulin domain. Mol Cell Biol 11:4627- 
4634. 
Kavanaugh, W.M., Klippel, A., Escobedo, J. A., and 
Williams, L.T. 1992. Modification of the 85- 
kilodalton subunit of phosphatidylinositol-3 ki- 
nase in platelet-derived growth factor-stimulated 
cells. Mol Cell Biol 12:3415-3424. 
Klippel, A., Escobedo, J. A., Fantl, W.J., and Wil- 
liams, L.T. 1992. The C-terminal SH2 domain of 
p85 accounts for the high affinity and specificity 
of the binding of phosphatidylinositol 3-kinase to 
phosphorylated platelet-derived growth factor /3- 
receptor. Mol Cell Biol 12:1451-1459. 
Mirda, D.P., Navarro, D., Paz, P., Lee, P.L., Pereira, L., 
and Williams, L.T. 1992. The fibroblast growth 
factor receptor is not required for herpes simplex 
virus type 1 infection. / Virol 66:448-457 . 
Muslin, A.J. , and Williams, L.T. 1991. Well-defined 
growth factors promote cardiac development in 
axolotl mesodermal explants. Development 
112:1095-1101. 
Peters, K.G., Marie, J., Wilson, E., Ives, H.E., Esco- 
bedo, J., Del Rosario, M., Mirda, D., and Wil- 
liams, L.T. 1992. Point mutation of an FGF re- 
ceptor abolishes phosphatidylinositol turnover 
and Ca^^ flux but not mitogenesis. Nature 
358:678-681. 
Peters, K.G., Werner, S., Chen, G., and Williams, 
L.T. 1992. Two FGF receptor genes are differen- 
tially expressed in epithelial and mesenchymal 
tissues during limb formation and organogenesis 
in the mouse. Development 1 14:233-243. 
Ueno, H., Gunn, M., Dell, K., Tseng, A., Jr., and Wil- 
liams, L.T. 1992. A truncated form of fibroblast 
growth factor receptor 1 inhibits signal transduc- 
tion by multiple types of fibroblast growth factor 
receptor, f Biol Chem 267:1470-1476. 
Werner, S., Duan, D.-S. R., de Vries, C, Peters, K., 
Johnson, D.E., and Williams, L.T. 1992. Differ- 
CELL BIOLOGY AND REGULATION 121 
