Deciphering the Secretory Pathway: Molecular Mechanisms, Physiological Relevance, and Therapeutic Opportunities

The secretory pathway is a fundamental cellular process that ensures the accurate delivery of hormones, growth factors, and transmembrane proteins to their functional destinations. Our research addresses a long-standing question: how do transmembrane receptors and their soluble ligands traverse this pathway to reach the cell surface or the extracellular space? Although expression patterns and downstream signaling of these signaling molecules are well characterized, the mechanisms that govern their trafficking along the secretory pathway remain poorly defined. To bridge this gap, our lab has developed systematic platforms to dissect cargo sorting and vesicular transport. A key achievement is the in vitro reconstitution of receptor and ligand packaging into transport vesicles. Combined with electron microscopy and vesicle proteomics, this innovative platform enables comprehensive analysis of vesicle composition, morphology, and cargo specificity. In this talk, I will present our recent advances using these approaches to elucidate the sorting and surface delivery of the transmembrane receptors Frizzled6 and EGFR, as well as the soluble ligands Sonic Hedgehog and insulin-like growth factor 2. These results reveal previously unrecognized pathways that control biosynthetic trafficking and link intracellular transport to signal transduction and tissue organization, providing a mechanistic basis for future physiological and translational studies.