Human rhomboid family‐1 geneRHBDF1participates in GPCR‐mediated transactivation of EGFR growth signals in head and neck squamous cancer cells

Abstract

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.

Human Rhomboid Family-1 Suppresses Oxygen-Independent Degradation of Hypoxia-Inducible Factor-1α in Breast Cancer

“…RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and RHBDF1 gene silencing results in apoptosis or autophagy in breast cancer or head and neck cancer cells and inhibition of xenograft tumor growth (11). RHBDF1 was found to participate in the modulation of Gprotein-coupled receptor-mediated transactivation of EGF receptor (12). These findings indicate that RHBDF1 may function as a regulatory protein involved in growth signal transduction.…”

“…In Drosophila, noncatalytic rhomboids were shown to prevent the cleavage of the substrates of rhomboid proteases by promoting their destabilization by endoplasmic reticulum-associated degradation (10). In human, RHBDF1 was shown to have a pivotal role in sustaining growth signals in epithelial cancers (11,12). RHBDF1 mRNA level is significantly elevated in clinical specimens of invasive ductal carcinoma of the breast, and RHBDF1 gene silencing results in apoptosis or autophagy in breast cancer or head and neck cancer cells and inhibition of xenograft tumor growth (11).…”

Lentivirus-mediated Silencing of Rhomboid Domain Containing 1 Suppresses Tumor Growth and Induces Apoptosis in Hepatoma HepG2 Cells

“…Intriguingly, in human, members of rhomboid intramembrane proteases have also been shown to play an important role in the activation of EGFR (Zou et al, 2009;Adrain et al, 2011). More importantly, the disruption of EGFR signaling by rhomboid family may lead to the alterations of the biological characteristics of cancers, including proliferation and invasion (Zou et al, 2009).…”

“…However, several investigations have provide strong evidence that rhomboid protease may play an important role in cancer cell growth and apoptosis. For example, human rhomboid family-1 (RHBDF1), a novel family member of rhomboid proteases, participates in the modulation of GPCR-mediated EGFR transactivation and disrupts growth signals in several cancer cell growth, including epithelial cancer, breast cancer, and head and neck squamous cancer cells (Yan et al, 2008;Zou et al, 2009). Rhomboid domain containing 1 (RHBDD1), an important gene highly expressed in the testis, is shown to participate in the cleavage of BIK and modulate BIK-medicated apoptosis (Wang et al, 2008).…”

516: Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells

“…EGF was previously found to strongly stimulate migration in several oral cancer cells, including E10 [12], and transactivation of EGFR has been found to be part of the mechanism of mitogenic effects of GPCRs in several cancer cells [20,21,30,37]. We now investigated the role of EGFR signalling in the stimulation of migration by LPA.…”