Growth factor action; signal transduction; protein processing
Two major areas of investigation are in progress in our laboratory. In the first, polypeptide growth factors, hormonal-like agents responsible for the regulation of growth and/or maintenance of viability of eukaryotic cells, and their receptors are being examined with respect to structure and mechanism. The action of NGF, EGF, and basic fibroblast growth factor (bFGF) on responsive cultured cells (primarily PC12 and germane mutants) is being determined utilizing receptor chimeras. This work includes specific analyses of the mutations in FGFR3 that lead to a variety of skeletal dysplasias. The second block of studies addresses the manner in which protein turnover in eukaryotic cells is regulated. The co- and post-translational modification of the amino termini of nascent polypeptide chains is a key part of these processes and studies on the isolation, characterization, cloning, and expression of several germane enzymes are in progress. The connection between these modifications and the ubiquitin-based mechanisms of protein degradation also are under investigation.
Y.Y. Wu and R.A. Bradshaw, PC12-E-2 Cells: A Stable Variant with Altered Responses to Growth Factor Stimulation, J. Cell. Physiol. 164, 522-532 (1995).
S. Raffioni and R.A. Bradshaw, Staurosporine Causes Epidermal Growth Factor to Induce Differentiation in PC12 Cells via Receptor Upregulation, J. Biol. Chem. 270, 7568-7572 (1995).
S.M. Arfin, R. L. Kendall, L. Hall, L.H. Weaver, A.E. Stewart, B.W. Matthews and R.A. Bradshaw, Eukaryotic Methionyl Aminopeptidases: Two classes of Cobalt-dependent Enzymes, Proc. Natl. Acad. Sci. USA 92, 7714-7718 (1995).
A. Vallesi, G. Giuli, R.A. Bradshaw, and P. Luporini, Autocrine Mitogenic Activity of Pheromones Produced by the Protozoan Ciliate Euplotes raikovi, Nature 376, 522-524 (1995).
D. Thomas and R.A. Bradshaw. 1997. Differential Utilization of ShcA Tyrosine Residues and Functional Domains in the Transduction of EGF-induced MAP kinase Activation in 293T Cells and NGF-induced Neurite Outgrowth in PC12 Cells: Identification of a New Grb2 Binding Site. J. Biol. Chem., 272:22293-22299.
L.M. Thompson, S. Raffioni, J.J. Wasmuth, and R.A. Bradshaw. 1997. Chimeras of the Native Form or Achondroplasia Mutant (G375C) of Human Fibroblast Growth Factor Receptor 3 Induce Ligand-Dependent Differentiation of PC12 Cells. Mol. Cell Biol., 17:4169-4177
Structural Biology and Molecular Biophysics