title: PHD3 regulates EGFR internalization and signalling in tumours.
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.
authors.affiliation: 1] Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany [2].
authors.forename: Boyan K
authors.initials: BK
authors.lastname: Garvalov
authors.affiliation: 1] Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany [3].
authors.forename: Franziska
authors.initials: F
authors.lastname: Foss
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Anne-Theres
authors.initials: AT
authors.lastname: Henze
authors.affiliation: 1] Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Bethani
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gräf-Höchst
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Devendra
authors.initials: D
authors.lastname: Singh
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Filatova
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Higinio
authors.initials: H
authors.lastname: Dopeso
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Seidel
authors.affiliation: 1] Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Damm
authors.affiliation: 1] Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany [3].
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.affiliation: 1] Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany [2].
authors.forename: Till
authors.initials: T
authors.lastname: Acker
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004705:Endocytosis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C486204:EPN2 protein, human; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C512478:EGFR protein, human; D066246:ErbB Receptors