CD317 Activates EGFR by Regulating Its Association with Lipid Rafts

Abstract

EGFR regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane. CD317 was upregulated in HCC cells, promoting cell-cycle progression and enhancing tumorigenic potential in a manner dependent on EGFR. Mechanistically, CD317 associated with lipid rafts and released EGFR from these ordered membrane domains, facilitating the activation of EGFR and the initiation of downstream signaling pathways, including the Ras-Raf-MEK-ERK and JAK-STAT pathways. Moreover, in HCC mouse models and patient samples, upregulation of CD317 correlated with EGFR activation. These results reveal a previously unrecognized mode of regulation for EGFR and suggest CD317 as an alternative target for treating EGFR-driven malignancies.Significance: Activation of EGFR by CD317 in hepatocellular carcinoma cells suggests CD317 as an alternative target for treating EGFR-dependent tumors.

Foxq1 promotes metastasis of nasopharyngeal carcinoma by inducing vasculogenic mimicry via the EGFR signaling pathway

“…For example, the long noncoding RNA, EGFR-AS1, was shown to directly binds EGFR mRNA, which promotes cell growth and metastasis through upregulating EGFR expression in renal cancer 44 . While a recent study has shown that CD317 is associated with lipid rafts, and activates EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane 45 . In this study, we demonstrated that Foxq1 directly binds to the EGFR promoter region and regulates its transcription.…”

The viral restriction factor tetherin/BST2 tethers cytokinetic midbody remnants to the cell surface

“…Alternatively, the function of BST2-dependent MBR tethering might be important only in specific cell types (such as during the development of the brain, where MBRs accumulate at specific stages) 6 or in pathological conditions (such as in tumor cells, where BST2 is frequently found upregulated). 62,63 Altogether, we identified a striking common function of BST2 in retaining virions and MBRs at the plasma membrane. In both cases, BST2/tetherin limits their release into the extracellular medium and their spread to distant cells.…”

Bioinformatic Analysis of Hepatocellular Carcinoma Cell Lines to the Efficacy of Nimotuzumab

“… 13 Zhang et al found that CD317 activates EGFR in resistant progress as well. 14 To explore the resistance mechanism in depth and apply the possibility of EGFR targeted drugs, our research analyzed six HCC cell lines (Hep 3B2.1–7, Li-7, PLC/PRF/5, SK-HEP-1, SNU-182, SNU-387) for sensitivity to nimotuzumab. Then we compared the RNA-seq differences between sensitive and resistant group cell lines.…”

“… 9–12 Some studies showed that the complex signaling pathways are the primary cause of drug resistance in HCC cells. 13 , 14 …”

“…[9][10][11][12] Some studies showed that the complex signaling pathways are the primary cause of drug resistance in HCC cells. 13,14 Nimotuzumab is a humanized IgG1 isotype anti-EGFR mAb with two ligands, while other anti-EGFR mAbs only have one, developed at the Center of Molecular Immunology in Cuba. 15 Nimotuzumab was approved for the treatment of glioma, esophageal cancer, squamous cell carcinoma of the head and neck and pancreatic cancer in Cuba and some of these conditions in China.…”