PHD3 regulates EGFR internalization and signalling in tumours

Boyan K. Garvalov, Franziska Foss, Anne-Theres Henze, Ioanna Bethani, Sabine Gräf-Höchst, Devendra Singh, Alina Filatova, Higinio Dopeso, Sascha Seidel, Miriam Damm, Amparo Acker-Palmer () and Till Acker ()
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Boyan K. Garvalov: Institute of Neuropathology, University of Giessen
Franziska Foss: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
Anne-Theres Henze: Institute of Neuropathology, University of Giessen
Ioanna Bethani: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
Sabine Gräf-Höchst: Institute of Neuropathology, University of Giessen
Devendra Singh: Institute of Neuropathology, University of Giessen
Alina Filatova: Institute of Neuropathology, University of Giessen
Higinio Dopeso: Institute of Neuropathology, University of Giessen
Sascha Seidel: Institute of Neuropathology, University of Giessen
Miriam Damm: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
Amparo Acker-Palmer: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
Till Acker: Institute of Neuropathology, University of Giessen

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Tumours exploit their hypoxic microenvironment to induce a more aggressive phenotype, while curtailing the growth-inhibitory effects of hypoxia through mechanisms that are poorly understood. The prolyl hydroxylase PHD3 is regulated by hypoxia and plays an important role in tumour progression. Here we identify PHD3 as a central regulator of epidermal growth factor receptor (EGFR) activity through the control of EGFR internalization to restrain tumour growth. PHD3 controls EGFR activity by acting as a scaffolding protein that associates with the endocytic adaptor Eps15 and promotes the internalization of EGFR. In consequence, loss of PHD3 in tumour cells suppresses EGFR internalization and hyperactivates EGFR signalling to enhance cell proliferation and survival. Our findings reveal that PHD3 inactivation provides a novel route of EGFR activation to sustain proliferative signalling in the hypoxic microenvironment.

Date: 2014
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DOI: 10.1038/ncomms6577

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