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Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells

Huafei Zou^*,, Sufi M. Thomas^,, Zhen-Wen Yan^*,, Jennifer R. Grandis^,, Andreas Vogt^, and Lu-Yuan Li^*,

^* Department of Pathology,

Department of Otolaryngology, and

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; and

University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA

¹Correspondence: University of Pittsburgh Cancer Institute, 5117 Centre Ave., G12C, Pittsburgh, PA 15213, USA. E-mail: lil{at}upmc.edu

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-, but not the production of latent TGF-, whereas engineered overexpression of RHBDF1 markedly accelerates the secretion of TGF-. 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, H., Thomas, S. M., Yan, Z.-W., Grandis, J. R., Vogt, A., Li, L.-Y. Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells.

Key Words: siRNA • mitogenesis • oncogenesis • secretion • therapeutic