Marsha R. Rosner, Ph.D.

Growth Factor Receptor Signaling Leading to Cell Growth, Cell Differentiation or Cell Death

Research Summary

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.

Selected Papers

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 20, 5392-5403.

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 278, 13061-13068.

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 15, 19-23.

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, 6296-6303.

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.