Objective Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) is a newly identified human gene that inhibits the epidermal growth factor receptor(EGFR), which on combining with a ligand, can drive tumor growth. This study investigated the interaction between human LRIG1 and EGFR and attempted to delineate the functions of as well as the mechanisms used by the extracellular(ECD) and cytoplasmic(CPD) domains of the human LRIG1 protein to downregulate human EGFR signaling activity.Methods Two constructed chimeric eukaryotic expression vectors, pIRES2-EGFP-3XFLAG-LRIG1-ET and p3FLAG-LRIG1-TC, encoding the extracellular and transmembrane regions(LRIG1-ET) and the transmembrane and cytoplasmic regions(LRIG1-TC), respectively, and the plasmid p3XFLAG-CMV-9-LRIG1 encoding full-length LRIG1(LRIG1-FL) were transfected into the human glioma cell line U251 or primary astrocytoma cells by using liposomes. The number and affinity of cell surface EGFR on transfected cells was determined by ~(125)I-EGF binding assay. Results The dissociation constant(KD) values for EGFR were higher, and the maximum increase was observed in the cells transfected into LRIG1-ET(1.36 folds). The number of maximal binding sites(Bmax) of the receptors was decreased in all transfected cells; the maximum decrease was noted in the cells transfected into LRIG1-FL(40.05%).Conclusion Both the ECD and CPD of LRIG1 are important to negate EGFR signaling. The ECD may interfere with the binding between EGFR and its ligand and facilitate the functions of CPD. The CPD may, when brought in proximity to EGFR, enhance receptor degradation. These two mechanisms can contribute to the downregulation of EGFR-mediated signaling by LRIG1. Objective Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a newly identified human gene that inhibits the epidermal growth factor receptor (EGFR), which on combining with a ligand, can drive tumor growth. This study investigated the interaction between human LRIG1 and EGFR and attempted to delineate the functions of as well as the mechanisms used by the extracellular (ECD) and cytoplasmic (CPD) domains of the human LRIG1 protein to downregulate human EGFR signaling activity. Methods Two constructed chimeric eukaryotic expression vectors, pIRES2- EGFP-3XFLAG-LRIG1-ET and p3FLAG-LRIG1-TC, encoding the extracellular and transmembrane regions (LRIG1-ET) and the transmembrane and cytoplasmic regions (LRIG1-TC), respectively, and the plasmid p3XFLAG-CMV-9-LRIG1 encoding Full-length LRIG1 (LRIG1-FL) were transfected into the human glioma cell line U251 or primary astrocytoma cells by using liposomes. The number and affinity of cell surface EGFR on transfected cells was determined by Results The dissociation constant (KD) values ​​for EGFR were higher and the maximum increase was observed in the cells transfected into LRIG1-ET (1.36 folds). The number of maximal binding sites (Bmax ) of the receptors was decreased in all transfected cells; the maximum decrease was noted in the cells transfected into LRIG1-FL (40.05%). Conclusion Both the ECD and CPD of LRIG1 are important to negate EGFR signaling. binding between EGFR and its ligand and facilitate the functions of CPD. The CPD may, when brought in proximity to EGFR, enhance receptor degradation. These two mechanisms can contribute to the downregulation of EGFR-mediated signaling by LRIG1.