Objective：This stuly aims to explore strategies for effectively studying the interaction between membrane receptors and extracellular ligands using fluorescence resonance energy transfer(FRET). Methods：Based on the model of interaction between LRP6 and WNT3A established by PDB and Zdock database，LRP6 was truncated without affecting the interaction between LRP6 membrane receptor and WNT3A；the signal peptides of LRP6 and WNT3A were reconstituted at the amino terminus of the fluorescent tag to avoid loss of the fluorescent tag due to signal peptide cleavage；flexible linker peptides was used to connect signal peptides，fluorescent tags， and mature proteins to attenuate the effects of fluorescent tags on subcellular localization and function of membrane receptors. Results：The above improvement strategy significantly enhanced the membrane localization signal of LRP6 fusion protein. The interaction between LRP6 and WNT3A in the cell membrane region could be clearly detected by FRET technology，and the average FRET efficiency reached 26.51%. Conclusion：This study provides new ideas and strategies for effectively using FRET technology to study the interaction between membrane receptors and extracellular ligands in living cells.