EGFRtoMITO
Financiado
EGFR signalling talks to mitochondria through contact sites
The integration of distinct internalization routes is crucial to determine the fate of plasma membrane (PM) receptors and the output of their signalling pathways. Contact sites between cellular organelles adds a further layer of r...
The integration of distinct internalization routes is crucial to determine the fate of plasma membrane (PM) receptors and the output of their signalling pathways. Contact sites between cellular organelles adds a further layer of regulation by creating microdomains that favour different signalling and metabolic pathways. These regulatory mechanisms are relevant to the epidermal growth factor receptor (EGFR). We found that EGFR internalization through non-clathrin endocytosis (NCE) leads primarily to receptor degradation and signal extinction, while clathrin-mediated endocytosis (CME) is mainly involved in EGFR recycling and sustaining signalling. Notably, internalization via NCE involves the formation of contact sites between the PM, the endoplasmic reticulum (ER) and the mitochondria, where EGF-dependent localized Ca2+ signalling occurs.
The founding hypothesis of this proposal is that the PM-ER-mitochondrial interface could represent a functional unit where direct cross-communication between EGFR signalling and mitochondria takes place. To investigate this hypothesis, we will use a three-tiered strategy aimed at elucidating:
1. the EGFR-dependent signalling that leads to NCE-ER-mitochondrial contact site formation and to local Ca2+ release, and the role of these contacts in EGFR endocytosis, signalling and fate;
2. the crosstalk between EGFR signalling and mitochondrial function at the PM-ER-mitochondrial interface by analysing the impact of EGFR-NCE on mitochondrial physiology and metabolism;
3. the relevance of NCE-ER-mitochondrial crosstalk to EGF-dependent cell physiological responses, e.g., migration, proliferation and differentiation, by exploiting isogenic cell derivatives from embryonic/pluripotent stem cells or ex vivo organoid cultures.
The verification of this hypothesis will expand our understanding of the impact of EGFR signalling on cellular functions not previously linked to this pathway and possibly impinging on cellular energetics and metabolism.
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Duración del proyecto: 72 meses
Fecha Inicio: 2021-06-14
Fecha Fin: 2027-06-30
Fecha Fin: 2027-06-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2021-06-14
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2020-COG:
ERC CONSOLIDATOR GRANTS
Cerrada
hace 4 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
UNIVERSITA DEGLI STUDI DI MILANO
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
141.07K€ |
Participante