Dataset Information
Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor ? membrane trafficking to promote breast cancer progression.
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ABSTRACT: Background
Epidermal growth factor receptor (EGFR) signalling is critical in epithelial cancer development. Human rhomboid family-1 (RHBDF1) facilitates the secretion of TGF?, an EGFR ligand, in breast cancer; however, the underlying mechanism remains unclear. We evaluated the role for RHBDF1 in clathrin-coated vesicle (CCV)-dependent pro-TGF? membrane trafficking in breast cancer cells upon stimulation by G-protein coupled receptor (GPCR) agonists.Methods
RHBDF1 was silenced in various breast cancer cells using shRNA. TGF? levels, subcellular localization, and secretion were evaluated using ELISA, immunofluorescent staining, and coimmunoprecipitation. Phosphorylation and expression of relevant proteins were measured by western blotting. RHBDF1-dependent cell viability and invasion were measured.Findings
RHBDF1 mediates GPCR agonist-induced EGFR phosphorylation by promoting TGF? secretion in various types of breast cancer cells. RHBDF1 not only mediates ADAM17-dependent shedding of TGF?, but is essential in membrane trafficking of pro-TGF?. RHBDF1 silencing results in blocking of clathrin uncoating from CCV, a crucial step for the plasma membrane release of pro-TGF?. Interaction of RHBDF1 with auxilin-2, a CCV protein, determines the recruitment of HSC70 to CCV to facilitate clathrin uncoating. RHBDF1 function is required for the proliferation and mobility of breast cancer cells upon stimulation by Sphingosine 1 Phosphate (S1P), a GPCR agonist. We demonstrate a significant correlation between RHBDF1 overexpression and EGFR activation in breast cancer tissues.Interpretation
RHBDF1 is an indispensable component of the protein trafficking machinery involved in GPCR-mediated EGFR transactivation, and is an attractive therapeutic target for cancer. FUND: National Natural Science Foundation of China (81,672,740 to ZSZ, 81,272,356 and 81,330,029 to LYL).
SUBMITTER: Li J
PROVIDER: S-EPMC6197618 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Publications
Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor α membrane trafficking to promote breast cancer progression.
EBioMedicine 20180929
<h4>Background</h4>Epidermal growth factor receptor (EGFR) signalling is critical in epithelial cancer development. Human rhomboid family-1 (RHBDF1) facilitates the secretion of TGFα, an EGFR ligand, in breast cancer; however, the underlying mechanism remains unclear. We evaluated the role for RHBDF1 in clathrin-coated vesicle (CCV)-dependent pro-TGFα membrane trafficking in breast cancer cells upon stimulation by G-protein coupled receptor (GPCR) agonists.<h4>Methods</h4>RHBDF1 was silenced in ...[more]
