Cell Homeostasis Through Inter-organelle Signaling Pathways: The Unfolded Protein Response
As they are being synthesized in the cytoplasm, proteins destined for secretion or for insertion into the plasma membrane are targeted to and enter the endoplasmic reticulum (ER) as unfolded, unmodified amino acid chains. Within the ER lumen, such nascent peptides are subject to modification, folding and assembly steps (protein processing) through contact with a variety of ER resident enzymes, chaperones, and other protein processing components. In order to meet changes in demand for protein processing capacity during their lifetimes, and also as a means to clear potentially toxic levels of misfolded proteins from the ER, cukaryotes employ a signaling pathway, referred to as the unfolded protein response pathway, or UPR, between the ER and the nucleus that can regulate the transcription of several critical protein processing genes.
The UPR pathway is remarkable on several levels including its use of unique regulatory molecules, its use of an unprecedented regulatory mRNA splicing step, and for its apparent influence on a diverse array of other cell activities. Research in my lab currently focuses on advancing our understanding of UPR signaling mechanisms and further, on how UPR signaling integrates with other regulatory pathways to effect cell homeostasis. To address these issues, we are taking cell biology, biochemical and genetic approaches to analyze the biochemistry of key UPR signaling components, to identify novel UPR signaling components, and to assess their specific physiological roles in the cell.
We are also interested in investigating potential roles of the UPR pathway in tumorgenesis. One can imagine that signaling through the UPR could support tumorgenesis in virtually any tissue by allowing the expanded protein processing capacity necessary to produce cellular proteins and secreted factors necessary to sustain rapid growth. While individual tumor types might require increased levels of differing sets of proteins, increased demand for protein processing in the ER would be common to many.