The long-term goal of our research program is to understand the molecular logic of signal transduction, focusing on proteins implicated in human disease. The laboratory currently emphasizes structure-function studies in Notch signaling and maintains an ongoing interest in other oncogenic signaling pathways. 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. Although Notch receptors are large and complex, all family members contain an extracellular ligand-binding domain, a conserved extracellular juxtamembrane region that maintains the receptor in a resting conformation prior to ligand-induced activation, and an intracellular ankyrin repeat domain required to activate transcription. Mutations in the juxtamembrane region cause increased signaling and occur frequently in human T-cell acute leukemias (T-ALL), identifying Notch as a therapeutic target in these tumors. Our current efforts are directed toward understanding how activation is induced by ligands, how Notch cooperates with other factors to regulate target gene transcription, and how to inhibit Notch1 as a potential treatment for the aberrant signaling that occurs in more than half of human T-ALLs.