Marsha R. Rosner, Ph.D.
Growth Factor Receptor Signaling Leading to Cell
Growth, Cell Differentiation or Cell Death
Growth factor-mediated signal transduction is a process
that is of fundamental importance in understanding cellular growth and
differentiation. In recent years, a number of laboratories including my
own have devoted considerable effort toward elucidating the mechanisms
by which initiation of signal transduction by growth factors is
regulated. We have focused many of our recent studies on the mechanisms
by which the epidermal growth factor (EGF) receptor is regulated, with
particular emphasis on heterologous regulation of exogenous growth
modulators such as novel tumor promoters, retinoids and transforming
growth factor-beta. Depending on the agent, this type of regulation can
be stimulatory at the level of genetic expression of the receptor, or
inhibitory at the level of biochemical regulation of receptor activity.
During the past few years we have been isolating and characterizing the
enzymes involved in the EGF signal transduction cascade, which are also
important in the regulation of the EGF receptor itself. We have also
investigated a number of growth modulators that alter transcription of
the EGF receptor, and we have identified the domains within the EGF
receptor promoter that are important for regulation by these agents. In
addition, we have cloned, expressed and characterized a growth factor
protease for transforming growth factor-alpha and insulin-related
factors from both human and Drosophila sources that is highly conserved
evolutionarily. This enzyme is a member of a newly emerging family of
metalloproteinases that act as processing enzymes in species ranging
from yeast to man. We plan to use this system to address the important
problem of regulation of signal transduction by proteolytic
degradation. Finally, we have focused our most recent efforts on
elucidation of the signal transduction cascades leading to the
differentiation of neuronal cells. Using conditionally immortalized CNS
cell lines that we have generated, we have demonstrated that EGF
stimulates growth but not differentiation of the cells, whereas
fibroblast-derived growth factor can induce neuronal differentiation at
the nonpermissive temperature. We are currently characterizing the
kinase cascade leading to neuronal differentiation by growth factors
and cloning novel genes that are regulated by this process.
Eves EM, Boise LH, Thompson CB, Wagner A, Hay N, and
Rosner MR. (1996). Apoptosis induced by differentiation or
serum-deprivation in an immortalized central nervous system neuronal
cell line. J. Neurochem., 67:1908-1920.
Morrison P, Chung K-C, and Rosner MR. (1996). Mutation
of di-leucine residues in the juxtamembrane region alters EGF receptor
expression. Biochemistry, 35:14618-14624.
Xiong W, Pestell RG, Rosner MR, and Hershenson MB.
(1997). Cyclin D1 is required for S phase traversal in bovine tracheal
myocytes. Am. J. Physiol. (Lung Cell. Mol. Physiol.), 272: L1205-1210.
*Chesneau V, *Perlman RK, Li W, Keller G-K, and Rosner
MR. (1997). Insulin-degrading enzyme does not require peroxisomal
localization for insulin degradation. Endocrinology, 138:3444-3451.
(*denotes equal author contribution).
Chao T-SO, Abe M, Hershenson MB, Gomes I, and Rosner MR.
(1997). Src tyrosine kinase mediates stimulation of Raf-1 and
mitogen-activated protein kinase by the tumor promoter thapsigargin.
Cancer Res., 57:3168-3173.
Kuo W-L, Chung K-C, and Rosner MR. (1997).
Differentiation of central nervous system neuronal cells by
fibroblast-derived growth factor requires at least two signaling
pathways: roles for Ras and Src. Mol. Cell. Biol., 17:4633-4643.
Xiong W, Pestell R, and Rosner MR. (1997). Role of
cyclins in neuronal differentiation of immortalized hippocampal cells.
Mol. Cell. Biol., 17:6585-6597.
Corbit KC, Soh JW, Yoshida K, Eves EM, Weinstein IB and
Rosner MR. (2000). Different protein kinase C isoforms
determine growth factor specificity in neuronal cells. Mol Cell Biol
Corbit KC, Trakul N, Eves EM, Diaz B, Marshall M and
Rosner MR. (2003). Activation of Raf-1 Signaling by Protein Kinase C
through a Mechanism Involving Raf Kinase Inhibitory Protein. J Biol Chem
Trakul N, Menard RE, Schade GR, Qian Z and Rosner MR.
(2005). Raf kinase inhibitory protein regulates Raf-1 but not B-Raf
kinase activation. J Biol Chem 280, 24931-24940.
Trakul N and Rosner MR. (2005). Modulation of the MAP
kinase signaling cascade by Raf kinase inhibitory protein. Cell Res
Cohen EE, Lingen MW, Zhu B, Zhu H, Straza MW, Pierce
C, Martin LE and Rosner MR. (2006). Protein kinase C zeta
mediates epidermal growth factor-induced growth of head and neck tumor
cells by regulating mitogen-activated protein kinase. Cancer Res 66,
Eves EM, Shapiro P, Naik K, Klein UR, Trakul N and
Rosner MR. (2006). Raf kinase inhibitory protein regulates aurora B
kinase and the spindle checkpoint. Mol Cell 23, 561-574.