Mechanisms of Neurotrophin Signal Transduction
Bruce D. Carter
Department of Biochemistry
Center for Molecular Neuroscience
418 Medical Research Building-II
The neurotrophins are a family of dimeric proteins, with nerve growth factor (NGF) as the prototypical member. These factors promote the survival, differentiation and, in some instances, proliferation of developing neuroblasts. As neurons mature and send axonal projections to their specific targets, where the neurotrophins are produced, they rely on these proteins for continued survival and further phenotypic specification. The neurotrophins exert their effects through binding to two types of receptors, the Trks, which have a tyrosine kinase domain, and a receptor referred to as p75, which is a member of the Fas/ TNF receptor family. Neurotrophin binding to Trk has been shown to activate canonical growth factor signaling pathways, although much remains to be determined regarding the regulation of these paths in neurons. In contrast to the Trks, neurotrophin binding to the p75 receptor has only recently been shown to activate a signaling pathway, which includes stimulation of a transcription factor (NFkB) and, surprisingly, apoptosis in specific cell types. However, the components of these signaling pathways remain to be determined.
The goal of our lab is to delineate the molecular mechanisms of neurotrophin signaling, particularly via the p75 receptor in neurons and their progenitors using a number of molecular and cellular approaches. To understand how receptor activation by these growth factors can lead to cellular responses such as NfkB activation and cell death, we are looking for intracellular signaling proteins. Recently, we identified a novel protein associated with the cytoplasmic domain of p75. Current studies are aimed at investigating its role in neurotrophin signal transduction. In addition, a transgenic approach is being used to determine the effects of gene deletion of this protein. Through structure-function analysis we are also assessing the domains and residues of the receptor involved in activating the signaling pathways. Further, since most neurons express both Trk and p75 and these have seemingly opposing actions (i.e. survival vs. apoptosis) we are also investigating the cross-talk between the signaling pathways. These studies are important not only for understanding the basic mechanisms of neural function, but are also relevant to ongoing clinical trials of neurotrophins in the treatment of neurodegenerative diseases.
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