The Nogo-B receptor promotes Ras plasma membrane localization and activation

• Published in: Oncogene 2017-06, Vol.36 (24), p.3406-3416
• Main Authors: Zhao, B, Hu, W, Kumar, S, Gonyo, P, Rana, U, Liu, Z, Wang, B, Duong, W Q, Yang, Z, Williams, C L, Miao, Q R
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/89; 13/95; 14; 14/19; 14/34; 14/63; 14/69; 38; 38/70; 38/77; 42; 59; 631/67/1347; 631/67/395; 631/80/86/2368; 64; 64/60; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell Membrane - metabolism; Cell membranes; Cell surface antigens; EGF Family of Proteins - metabolism; Epidermal growth factor; Female; Fibroblasts; Fibrosarcoma; Fibrosarcoma - genetics; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Human Genetics; Humans; Hydrophobicity; Internal Medicine; Kinases; Localization; Medicine; Medicine & Public Health; Membranes; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; NIH 3T3 Cells; Nogo protein; Oncology; original-article; Phenotypes; Plasma; Protein Prenylation; Ras protein; ras Proteins - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Rodents; Signal Transduction; Tumorigenesis; Tyrosine; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.484

The localization of prenylated Ras at the plasma membrane promotes activation of Ras by receptor tyrosine kinases and stimulates oncogenic signaling by mutant Ras. The Nogo-B receptor (NgBR) is a transmembrane receptor that contains a conserved hydrophobic pocket. Here, we demonstrate that the NgBR promotes the membrane accumulation of Ras by directly binding prenylated Ras at the plasma membrane. We show that NgBR knockdown diminishes the membrane localization of Ras in multiple cell types. NgBR overexpression in NIH-3T3 fibroblasts increases membrane-associated Ras, induces the transformed phenotype in vitro , and promotes the formation of fibrosarcoma in nude mice. NgBR knockdown in human breast cancer cells reduces Ras membrane localization, inhibits epidermal growth factor (EGF)-stimulated Ras signaling and diminishes tumorigenesis of xenografts in nude mice. Our data demonstrate that NgBR is a unique receptor that promotes accumulation of prenylated Ras at the plasma membrane and promotes EGF pathways.