Stephen Charles Blacklow, Ph.D., M.D.

For many years, my laboratory has focused on understanding fundamental mechanisms of signal transduction at the structural and molecular level. Our work has emphasized the investigation of how information is communicated across the plasma membrane. Current studies in the laboratory center on the Notch pathway, which relies on cell-cell contact to transmit a signal. Notch signals influence a wide spectrum of cell fate decisions, both during development and in adult organisms, yet dysregulated Notch signaling has been implicated in the pathogenesis of a number of human cancers. The Notch proteins are single-pass transmembrane receptors that convey signals upon activation by transmembrane ligands expressed on neighboring cells. Ligand binding initiates signaling by triggering a process called regulated intramembrane proteolysis, releasing the intracellular part of Notch (ICN) from the membrane. In canonical Notch signaling, ICN ultimately enters the nucleus, where it assembles into a transcriptional activation complex to induce the expression of Notch target genes. Our current efforts are directed toward answering a number of unresolved questions about how proteins genetically implicated in the Notch pathway modulate signaling in normal and cancer contexts. Priorities include understanding the detailed sequence of events that occur at the plasma membrane upon signal activation, uncovering the molecular mechanism of normal and pathogenic activation of Notch receptors by ADAM-family metalloproteases, elucidating how Notch cooperates with other nuclear factors to control target gene transcription, and understanding how negative feedback regulators fine-tune signaling.