The long-term goal of our research program is to understand the molecular logic of cell-surface receptors, focusing on proteins implicated in human disease. The laboratory currently emphasizes structure-function studies in Notch signaling and maintains an ongoing interest in proteins of the LDL receptor family. Notch proteins are single-pass transmembrane receptors that convey signals upon activation by transmembrane ligands expressed on neighboring cells. The signals transduced by Notch receptors play a central role in cell fate decisions both during embryonic development and in adult tissue homeostasis. 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 understanding how activation is induced by ligands and how Notch cooperates with other factors to regulate target gene transcription. The LDL receptor is the primary mechanism for uptake of cholesterol-carrying particles into cells. This receptor also serves as a prototype for a large class of related proteins that participate in Wnt signaling and that control cortical migration in development. Mutations in the gene encoding the LDL receptor lead to the genetic disorder familial hypercholesterolemia (FH). FH heterozygotes carry a substantially increased risk for cardiovascular disease. Untreated homozygous FH leads to death at an early age, and is the most compelling evidence supporting the causal link between elevated serum cholesterol levels and atherosclerosis. LDL receptor-related proteins control processes as diverse as lipoprotin uptake, clearance of protein complexes from plasma, and transmission of extracellular signals in development. We are particularly interested in two LDL receptor-related proteins that participate in Wnt signaling and that control cortical migration in developing neurons.