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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
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PHD3 regulates EGFR internalization and signalling in tumours
Boyan K Garvalov1, Franziska Foss2, Anne-Theres Henze3
11] Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany [2].
Nature Communications
|November 26, 2014
Summary
Tumours use hypoxia to become aggressive. Prolyl hydroxylase PHD3 controls epidermal growth factor receptor (EGFR) internalization, restraining tumour growth by regulating EGFR activity in hypoxic conditions.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumours utilize the hypoxic microenvironment to promote aggressive phenotypes.
- Mechanisms by which tumours overcome hypoxia-induced growth inhibition are not fully understood.
- Prolyl hydroxylase PHD3 is hypoxia-regulated and implicated in tumour progression.
Purpose of the Study:
- To identify PHD3 as a regulator of epidermal growth factor receptor (EGFR) activity.
- To elucidate the role of PHD3 in controlling EGFR internalization and tumour growth.
- To understand the implications of PHD3 inactivation in the hypoxic tumour microenvironment.
Main Methods:
- Investigated the role of PHD3 in regulating EGFR activity.
- Examined the association of PHD3 with endocytic adaptor Eps15.
- Assessed the impact of PHD3 loss on EGFR internalization, signalling, proliferation, and survival in tumour cells.
Main Results:
- PHD3 acts as a scaffolding protein, associating with Eps15 to promote EGFR internalization.
- Loss of PHD3 suppresses EGFR internalization, leading to EGFR hyperactivation.
- PHD3 inactivation enhances tumour cell proliferation and survival.
Conclusions:
- PHD3 is a central regulator of EGFR activity through the control of EGFR internalization.
- PHD3 inactivation offers a novel mechanism for EGFR activation in hypoxic tumours.
- PHD3 plays a critical role in restraining tumour growth within a hypoxic microenvironment.
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