Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells.
Epidermal growth factor receptor (EGFR) is an activated oncogene in many cancers. It can be transactivated by ligands of G protein-coupled receptors (GPCRs). We show here that a novel gene, human rhomboid family-1 (RHBDF1), which was recently reported to have a pivotal role in epithelial cancer cell growth in culture and in xenograft tumors, participates in the modulation of GPCR-mediated EGFR transactivation. The RHBDF1 protein localizes mainly in the endoplasmic reticulum. Silencing the RHBDF1 gene in head and neck squamous cancer cell line 1483 cells with siRNA causes an inhibition of gastrin-releasing peptide (GRP) -induced phosphorylation of EGFR and EGFR-dependent signaling proteins p44/42 MAPK and AKT, accompanied by an inhibition of GRP-induced survival, proliferation, and invasion of the cells. The EGFR signaling pathway itself remains intact, however, as the cells remain responsive to exogenous EGF. In addition, RHBDF1 gene silencing disrupts GRP-stimulated secretion of EGFR ligand TGF-alpha, but not the production of latent TGF-alpha, whereas engineered overexpression of RHBDF1 markedly accelerates the secretion of TGF-alpha. These findings are consistent with the view that RHBDF1 is critically involved in a GPCR ligand-stimulated process leading to the activation of latent EGFR ligands.
Zou
Huafei
H
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Thomas
Sufi M
SM
Yan
Zhen-Wen
ZW
Grandis
Jennifer R
JR
Vogt
Andreas
A
Li
Lu-Yuan
LY
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
D008024:Ligands; D008565:Membrane Proteins; C081962:RHBDF1 protein, human; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D016211:Transforming Growth Factor alpha; D019886:Gastrin-Releasing Peptide; D066246:ErbB Receptors