A MULTIORGANELLE PLATFORM REGULATES EGFR ENDOCYTOSIS AND SIGNALLING
type: CreativeWork
description: Endocytosis plays a crucial role in regulating the signalling of the epidermal growth factor receptor (EGFR). The internalization of the EGFR can occur through different mechanisms. Clathrin-mediated endocytosis (CME) operates at all concentrations of EGF and in all cell contexts, directing the majority of receptors towards recycling. In contrast, non-clathrin endocytosis (NCE) is activated only at high (but physiological) EGF concentrations, alongside CME, and leads to the degradation of EGFR. Thus, the NCE pathway can serve as an intrinsic cellular system to suppress EGFR levels and signalling, which could be particularly relevant in situations where the receptor or its ligands are excessively upregulated, such as in cancer. Through a proteomics investigation of EGFR-loaded NCE vesicles coupled with RNA interference screening, several functional regulators of NCE have been discovered, including the endoplasmic reticulum (ER)-shaping factor reticulon-3 (RTN3) and various mitochondrial proteins. RTN3 plays a critical role in EGFR internalization via NCE by promoting the formation of contact sites between the ER and the plasma membrane (PM). These contact sites are essential for the formation and elongation of NCE intermediates known as tubular invaginations (TIs). Calcium, released from the ER at these sites through the inositol trisphosphate receptor (IP3R), is required, along with the dynamin, for the fission of TIs and the completion of EGFR-NCE. Preliminary data from our laboratory suggested the possible involvement of mitochondria in EGFR-NCE: a significant enrichment in mitochondrial proteins was observed in isolated NCE vesicles. Electron microscopy (EM) analysis of PM-ER contact sites also revealed the presence of mitochondria adjacent to these structures. Hence, the main objectives of this thesis were to investigate the precise role of mitochondria in EGFR-NCE and to gain an understanding of the potential crosstalk between EGFR signalling and the specific s…
abstract: Endocytosis plays a crucial role in regulating the signalling of the epidermal growth factor receptor (EGFR). The internalization of the EGFR can occur through different mechanisms. Clathrin-mediated endocytosis (CME) operates at all concentrations of EGF and in all cell contexts, directing the majority of receptors towards recycling. In contrast, non-clathrin endocytosis (NCE) is activated only at high (but physiological) EGF concentrations, alongside CME, and leads to the degradation of EGFR. Thus, the NCE pathway can serve as an intrinsic cellular system to suppress EGFR levels and signalling, which could be particularly relevant in situations where the receptor or its ligands are excessively upregulated, such as in cancer. Through a proteomics investigation of EGFR-loaded NCE vesicles coupled with RNA interference screening, several functional regulators of NCE have been discovered, including the endoplasmic reticulum (ER)-shaping factor reticulon-3 (RTN3) and various mitochondrial proteins. RTN3 plays a critical role in EGFR internalization via NCE by promoting the formation of contact sites between the ER and the plasma membrane (PM). These contact sites are essential for the formation and elongation of NCE intermediates known as tubular invaginations (TIs). Calcium, released from the ER at these sites through the inositol trisphosphate receptor (IP3R), is required, along with the dynamin, for the fission of TIs and the completion of EGFR-NCE. Preliminary data from our laboratory suggested the possible involvement of mitochondria in EGFR-NCE: a significant enrichment in mitochondrial proteins was observed in isolated NCE vesicles. Electron microscopy (EM) analysis of PM-ER contact sites also revealed the presence of mitochondria adjacent to these structures. Hence, the main objectives of this thesis were to investigate the precise role of mitochondria in EGFR-NCE and to gain an understanding of the potential crosstalk between EGFR signalling and the specific s…
author: SALVI MESA, DEBORAH
language: eng
keywords: endocytosi, RTK, EGFR, contact site, mitochondria, Settore BIO/10 - Biochimica
date published: 2023-12-12
date modified: 2026-07-27T20:18:43Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1018170

PropertyValue
property ID: DOI
value: 10.13130/salvi-mesa-deborah_phd2023-12-12