Mathematical Biology Seminar Benjamin Myers, University of Utah, Wednesday, September 17, 2025 12:30 pm in LCB 222 Unconventional Mechanisms of Cell-cell Communication in Development and Cancer Abstract: The Hedgehog (Hh) signaling pathway is a central regulator of tissue growth and patterning, and its misregulation underlies several common cancers, including those of the skin and brain. A key control point is the receptor Smoothened (SMO), which is formally a member of the G protein-coupled receptor (GPCR) superfamily but does not follow the usual GPCR playbook. For decades, the rules by which SMO becomes active and transmits signals inside the cell have been unclear. I will discuss recent work from my lab that reveals two unexpected features of SMO regulation: (1) activation depends on specific cholesterol molecules embedded in the membrane, and (2) SMO directly controls protein kinase A (PKA) activity through an unprecedent mechanism of physically blocking the kinase's activity. Similar mechanisms also operate in the Wnt pathway, another crucial regulator of development, stem cell biology, and cancer. These results highlight how developmental and cancer signaling cascades use lipids and disordered protein motifs to encode switch-like responses while also preventing unwanted crosstalk with other cellular pathways. Beyond clarifying long-standing puzzles in developmental and cancer biology, this perspective suggests new ways to model the signaling logic underlying cell-cell communication and to design therapies that exploit unconventional regulatory principles.