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.

中文翻译：

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4.1B 通过与细胞内近膜段的 EGFR P13 区域结合来抑制癌细胞增殖。


背景技术胃癌(GC)在全世界范围内具有高发病率和死亡率。然而，调节胃癌发生的潜在机制在很大程度上尚不清楚。 4.1B 是在膜和细胞骨架界面处发现的衔接蛋白。先前的研究表明 4.1B 具有肿瘤抑制作用。结果 我们发现大多数 GC 患者中 4.1B 表达降低或消失。它的表达模式与肿瘤大小、TNM 分期和总生存期 (OS) 密切相关。我们进一步表明，4.1B 通过阻碍 EGFR/MAPK/ERK1/2 和 PI3K/AKT 通路来抑制两种 GC 细胞系 MGC-803 和 MKN-45 的增殖。在源自野生型 (WT) 和 4.1B 敲除 (BKO) 小鼠的永生化小鼠胚胎成纤维细胞 (MEF) 中也观察到类似的表型。此外，免疫荧光 (IF) 染色和 Co-IP 显示蛋白 4.1B 与 EGFR 结合。此外，4.1B的FERM结构域通过EGFR的细胞内近膜(JM)区段的起始13个氨基酸(P13)与EGFR相互作用。 4.1B与EGFR的结合抑制了EGFR的二聚化和自磷酸化。结论我们目前的工作表明，4.1B 通过与 EGFR 结合并通过 EGFR/MAPK/ERK1/2 途径抑制 EGFR 功能，在 GC 细胞增殖中发挥重要的调节作用。我们的研究结果为GC的发展和进展机制提供了新的见解。