Van Andel Research Institute

Understanding WNT9A/FZD9 Trafficking and Signaling - Cell to Cell Signaling Is Fundamental to All Multicellular Life. Secreted Signaling Molecules From One Cell Are Able to Communicate With Other Cells Through Interaction With Receptors on the Surface, Which Interpret and Transduce These Signals. One Such Class of Secreted Signaling Molecules Is Encoded by the WNT Gene Family. These Protein Products Drive a Plethora of Cellular Processes, Including Cellular Symmetry, Proliferation, Tissue Polarity and Stem Cell Maintenance. This Variety of Processes Occurs Using Conserved Intracellular Machinery to Program These Outputs, Indicating a Need for Complex Control at the Level of the Cell Membrane. at Least Part of the Regulation of This Signaling Complexity Lies in the Multiple Genes Encoding Specific Ligands (19 in Mammals) and Receptors (10 in Mammals). However, the Specific Mechanisms That Start With the Association of Various Ligands and Receptors at the Membrane, and Lead to Nuclear Transcriptional Activity Are Incompletely Understood. One of the Missing Links in This Aspect Is to Decipher How the Receptor Complex Is Internalized by the Cell, Where It Is Trafficked to, and How These Events Lead to Diverse Transcriptional Outputs. This System of Ligand-receptor Inputs Leading to Diverse Outputs Is Likely Dependent on the Composition of the Receptor Complex, and the Cellular Context of the Signal. Deciphering This Code Will Be Crucial to Our Understanding of How Cells Receive and Transduce Specific Signals. This Proposal Aims to Characterize the Communication Between Trafficking of a Specific WNT Signaling Receptor Complex, and Activation of Transcription in the Nucleus. Although It Is Known That Pairing a WNT Ligand and Frizzled (FZD) Receptor Is Required for the Transduction of Many (if Not Most) WNT Signals, Our Understanding of the Mechanisms Through Which Specific Wnt/fzd Pairings Allow the Transcriptional Activator Ss-catenin (ss-cat) to Enter the Nucleus Is Lacking. We Have Developed a Novel System to Study Specific Signal Transduction of This Nature by Fluorescently Labeled the WNT Ligand, FZD Receptor, and the Transcriptional Activator Ss-cat. This Is Based on Our Previous Studies Which Have Indicated That There Is an Exquisitely Specific Pairing of the Ligand WNT9A With the Receptor Frizzled (FZD)9B, and That Specificity of This Signal Is Conferred by the Epidermal Growth Factor Receptor (egfr). This Proposal Aims to Further Define the Mechanism of WNT9A/FZD9B Signal Transduction by Studying the Intracellular Trafficking of This Receptor Complex, and Coupling This to Ss-cat Movements. by First Understanding How One Specific Wnt/fzd Pairing Establishes a Specific Signal, We Can Generate a Model for Further Testing Other Wnt/fzd Complexes in Different Cellular Contexts. Furthermore, Cell Signaling Events Often Cross-over to Other Pathways; These Findings Could Certainly Impact Our Understanding of How Other Receptor-ligand Complexes Lead to Diverse Outputs in Cells. the Pi Has Expertise in WNT Signaling and Cell Biology, as Well as Experience With Mentoring Students to Publications in These Areas. Successful Completion of These Projects Set the Pi and Her Lab Up to Be Leaders in the Field of WNT Signaling, and for Long-term Success in the Field.