Sending and Receiving Hedgehog and Wnt Signals 

Seminar Details

Host: Dr. Xuewu Sui

Time: 4:00pm-5:00pm

Location: BICH Rm 108

Seminar Abstract

Hedgehog and Wnt proteins are secreted, lipid-modified morphogens fundamental to development and disease. Lipid modifications are pivotal to every aspect of Hedgehog and Wnt biology, from biogenesis and intracellular trafficking in producing cells to secretion, extracellular distribution, and ultimately reception and pathway activation in target cells. These processes rely on a dedicated network of lipid-dependent interactors, through which lipid-modified ligands are exchanged via rapid handoff. In recent years, we determined a cryo-EM structure capturing the transition state of Sonic Hedgehog (SHH) transfer from its coreceptor GAS1 to the receptor Patched1 (PTCH1), uncovering an unexpected catalytic role of GAS1 in assembling the signaling-competent SHH–PTCH1 complex. In parallel, we demonstrated that two distinct extracellular Wnt carriers, SFRPs and WIF1, facilitate Wnt release from the membrane transporter Wntless (WLS), forming soluble, active Wnt–carrier complexes. We further showed that glypicans (GPCs), coreceptors on responding cells, catalyze the transfer of Wnts from these carriers to Frizzled (FZD) receptors, thereby initiating pathway activation. This mechanism resembles the secretion and reception of dually lipidated Hedgehog ligands, which we previously elucidated through the roles of SCUBE2 and GAS1. Finally, we determined high-resolution cryo-EM structures of WLS bound to Wnt5a and in its Wnt-release state. WLS undergoes dramatic conformational changes topologically reminiscent of GPCR activation to release Wnt. Using newly developed quantitative assays, we demonstrated that all three Wnt–WLS interfaces are indispensable for Wnt trafficking, secretion, and pathway activation. Together, these studies establish a mechanistic paradigm for the biogenesis, secretion, reception, and regulation of lipid-modified morphogens.