4.1B suppresses cancer cell proliferation by binding to EGFR P13 region of intracellular juxtamembrane segment

• Main Authors: Fumin Xue, Chao An, Lixiang Chen, Gang Liu, Feifei Ren, Xinhua Guo, Haibin Sun, Lu Mei, Xiangdong Sun, Jinpeng Li, Youcai Tang, Xiuli An, Pengyuan Zheng
• Format: Article
• Language: English
• Published: BMC 2019-09-01
• Series: Cell Communication and Signaling
• Subjects: Gastric cancer; Protein 4.1B; EGFR; Sp1; Tumor suppressor
• Online Access: http://link.springer.com/article/10.1186/s12964-019-0431-6

Abstract Background Gastric cancer (GC) has high incidence and mortality worldwide. However, the underlying mechanisms that regulate gastric carcinogenesis are largely undefined. 4.1B is an adaptor protein found at the interface of membrane and the cytoskeleton. Previous studies demonstrated that 4.1B serves as tumor suppressor. Results We showed that 4.1B expression was decreased or lost in most GC patients. The expression pattern of it was tightly correlated with tumor size, TNM stage and overall survival (OS). We further showed that 4.1B inhibited the proliferation of two GC cell lines, MGC-803 and MKN-45, by impeding the EGFR/MAPK/ERK1/2 and PI3K/AKT pathways. A similar phenotype was also observed in immortalized mouse embryonic fibroblasts (MEF) derived from wild type (WT) and 4.1B knock-out (BKO) mice. Additionally, immunofluorescence (IF) staining and Co-IP showed that protein 4.1B bound to EGFR. Furthermore, the FERM domain of 4.1B interacted with EGFR through the initial 13 amino acids (P13) of the intracellular juxtamembrane (JM) segment of EGFR. The binding of 4.1B to EGFR inhibited dimerization and autophosphorylation of EGFR. Conclusion Our present work revealed that 4.1B plays important regulatory roles in the proliferation of GC cells by binding to EGFR and inhibiting EGFR function through an EGFR/MAPK/ERK1/2 pathway. Our results provide novel insight into the mechanism of the development and progression of GC.