Harvard University, A.B. Biochemistry, 1972;
Massachusetts Institute of Technology, Ph.D. Biochemistry, 1978
Growth factor-mediated signal transduction is a process that is of fundamental importance in understanding cellular growth, differentiation and cell death. Recently, we have focused considerable effort toward understanding the signals by which growth factors promote cell differentiation or cell death. As a model system, we developed a rat hippocampal neuronal cell line (H19-7) that is conditionally immortalized by the expression of a temperature- sensitive large T antigen. These cells undergo proliferation in response to EGF, and differentiation in response to FGF. Following differentiation, the cells also undergo differentiation-induced cell death, similar to what takes place in vivo during neuronal maturation. Although the highly conserved Ras/Raf/MAP kinase signal transduction pathway has been implicated in both cell growth and differentiation, our studies have shown that activation of the classic MAP kinases is not sufficient and may not even be necessary for neuronal differentiation. One possible explanation is that novel signaling molecules are required. In support of this hypothesis, we have recently identified a novel Elk1 kinase that is activated by Raf, and we are currently cloning and characterizing this kinase. This work represents the first direct evidence that Raf can activate a signaling cascade that is distinct from the classic MAP kinases. In addition, we also cloned and sequenced a novel MAP kinase that is expressed primarily in many tissues including brain. This MAP kinase, termed ERK7, has an extended carboxy terminus that contains SH3 binding motifs, and interactions via its C-terminal tail, rather than extracellular-mediated signal transduction, regulate its activity, its localization and its function. Thus, this new MAP kinase represents a novel mechanism by which growth factor signals are regulated. We have also identified other signaling pathways that promote cell growth, differentiation or cell death, and we have been developing new approaches to test these signaling cascades in vivo. These studies will increase our understanding of the mechanisms by which cell differentiation and survival is regulated, and provide targets for potential chemical agents that can be used to control growth-related processes.