Dataset Information

Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3).

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.

SUBMITTER: Amessou M

PROVIDER: S-EPMC5346708 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3).

Amessou Mohamed M Ebrahim Abdul Shukkur AS Dilly Ashok A Joseph Melvin M Tabolina Marina M Chukkapalli Sahiti S Meroueh Louay L Syed Joseph T JT Liddane Allison A Lang Siera Lanae SL Al-Katib Ayad A Kandouz Mustapha M

Oncotarget 20161101 48

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 ...[more]

PMID: 27811356

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is a devastating disease with a heterogeneous prognosis, and the molecular mechanisms underlying tumor progression remain elusive. Mammalian Eps15 homology domain 1 (EHD1) plays a promotive role in tumor progression, but its role in cancer angiogenesis remains unknown. This study thus explored the role of EHD1 in angiogenesis in NSCLC.MethodsThe changes in angiogenesis were evaluated through human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation assays. The impact of EHD1 on β2-adrenoceptor (β2AR) signaling was evaluated by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and enzyme-linked immunosorbent assay (ELISA). The interaction between EHD1 and β2AR was confirmed by immunofluorescence (IF) and coimmunoprecipitation (Co-IP) experiments, and confocal microscopy immunofluorescence studies revealed that β2AR colocalized with the recycling endosome marker Rab11, which indicated β2AR endocytosis. Xenograft tumor models were used to investigate the role of EHD1 in NSCLC tumor growth.ResultsThe microarray analysis revealed that EHD1 was significantly correlated with tumor angiogenesis, and loss- and gain-of-function experiments demonstrated that EHD1 potentiates HUVEC proliferation, migration and tube formation. EHD1 knockdown inhibited β2AR signaling activity, and EHD1 upregulation promoted vascular endothelial growth factor A (VEGFA) and β2AR expression. Interestingly, EHD1 interacted with β2AR and played a novel and critical role in β2AR endocytic recycling to prevent receptor degradation. Aberrant VEGFA or β2AR expression significantly affected EHD1-mediated tumor angiogenesis. The proangiogenic role of EHD1 was confirmed in xenograft tumor models, and immunohistochemistry (IHC) analysis confirmed that EHD1 expression was positively correlated with VEGFA expression, microvessel density (MVD) and β2AR expression in patient specimens.ConclusionCollectively, the data obtained in this study suggest that EHD1 plays a critical role in NSCLC angiogenesis via β2AR signaling and highlight a potential target for antiangiogenic therapy.

Dataset Information

Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3).

Publications

Spatio-temporal regulation of EGFR signaling by the Eps15 homology domain-containing protein 3 (EHD3).

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