Abstract
The epidermal growth factor (EGF) receptor EGFR is a major receptor tyrosine kinase whose role in gliomagenesis is well established. We have recently identified EHD3 [Eps15 homology (EH) domain-containing protein 3], an endocytic trafficking regulatory protein, as a putative brain tumor suppressor. Here, we investigate the underlying mechanisms, by establishing a novel mechanistic and functional connection between EHD3 and the EGFR signaling pathway. We show that, in response to stimulation with the EGF ligand, EHD3 accelerates the rate of EGFR degradation by dramatically increasing its ubiquitination. As part of this process, EHD3 also regulates EGFR endosomal trafficking by diverting it away from the recycling route into the degradative pathway. Moreover, we found that upon EGF activation, rather than affecting the total MAPK and AKT downstream signaling, EHD3 decreases endosome-based signaling of these two pathways, thus suggesting the contribution of EHD3 in the spatial regulation of EGFR signaling. This function explains the higher sensitivity of EHD3-expressing cells to the growth-inhibitory effects of EGF. In summary, this is the first report supporting a mechanism of EHD3-mediated tumor suppression that involves the attenuation of endosomal signaling of the EGFR oncogene.
Highlights
The National Cancer Institute reports an estimated 22,850 new cases and 15,320 deaths from brain and other Central Nervous System (CNS) cancers in the US in 2015
When examining the epidermal growth factor receptor (EGFR) mRNA transcript by real time RT-PCR, we found no significant differences in EGFR expression between Dox-induced and –non induced control cells (Figure 1C), suggesting that the effect of EHD3 on EGFR expression is post-transcriptional and involves an increase in the EGFR protein levels
As a follow up mechanistic investigation, and based on the reported role of the Eps15 homology domain-containing (EHD) family of proteins in endocytic trafficking [9, 23], we hypothesized that EHD3 might undergo its functions via regulating the trafficking of receptor tyrosine kinases (RTKs), and their signaling ability and functions
Summary
Gov/cancertopics/types/brain) reports an estimated 22,850 new cases and 15,320 deaths from brain and other Central Nervous System (CNS) cancers in the US in 2015. In 2012, there were 256,000 new cases diagnosed (http://www.wcrf.org/int/cancer-factsfigures/worldwide-data). GBM is a poorly differentiated astrocytic tumor, highly heterogeneous, extremely invasive and showing a complex biology [3]. GBM is characterized by an amplification and/or mutation of wild-type epidermal growth factor receptor (EGFR), amplification of the platelet-derived growth factor (PDGF) and receptors (PDGFRα/β), mutations of the IDH1 and IDH2 genes or loss of tumor suppressor genes such as p53, PTEN or p16Ink4a. EGFR is known as a key Receptor Tyrosine Kinase (RTK) and a therapeutic target in many cancers including gliomas [5,6,7]
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