Indirect cell-cell interactions mediated by secreted proteins and their plasma membrane receptors are crucial for regulating intercellular signaling. This study develops an interaction-guided crosslinking (IGC) chemical proteomics approach to identify ligand-receptor interactions in situ. Using glycan-based ligation and click chemistry, IGC achieves high sensitivity, identifying ligand-receptor complexes from a small number of cells (0.1 million) using minimal secreted ligand (10 ng). This allowed unbiased identification of ligand-receptor complexes, revealing a novel interaction between pancreatic cancer cell-secreted urokinase (PLAU) and neuropilin 1 (NRP1) on pancreatic cancer-associated fibroblasts. IGC provides a valuable tool for systematically exploring new ligand-receptor pairs and deciphering critical intercellular signaling events.

Jiangnan Zheng, Zhendong Zheng, Changying Fu, Yicheng Weng, An He, Xueting Ye, Weina Gao, Ruijun Tian