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Sara Sigismund, Ph.D. - "Organelle communication regulates EGFR endocytosis and signaling output"

Dipartimento di Oncologia ed Emato-oncologia, Università degli Studi di Milano and IEO, Istituto Europeo di Oncologia, Milano, Italy
When Oct 02, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Short CV

The integration of distinct endocytic routes is critical to regulate receptor signaling. At high dose of ligand, Epidermal Growth Factor Receptor (EGFR) is internalized through non-clathrin endocytosis (NCE), in addition to clathrin-mediated endocytosis (CME). Importantly, while CME mainly results in EGFR recycling and signaling, NCE targets the majority of the receptors to degradation. Mechanistically, NCE relies on the formation of ER-PM contact sites induced by EGFR activation and dependent on the ER-shaping factor reticulon 3 (RTN3), which serve as anchor sites for PM invagination, as well as spots of localized Ca2+ signaling. Triggering of NCE correlates with the activation of phospholipase enzymes, PLCg1 and PLCg2, suggesting that these signaling enzymes are key determinants in NCE. Indeed, the local Ca2+ release at PM-ER contact sites is mediated by inositol trisphophate receptor (IP3R) and is affected by PLC-inhibitors. EGF-induced Ca2+ isin turnneeded for EGFR-NCE to proceed, finally destining receptors to lysosomal degradation. Thus, NCE is critical to restrict EGFR signaling in condition of high ligand availability; in this view, NCE might work as a tumor suppressor pathway whose subversion could contribute to aberrant EGFR signaling and tumor development. However, this modality of internalization integrates numerous cellular functions and compartments - including PM, ER and mitochondria - with possible impact on Ca2+ signaling propagation, mitochondria dynamics and cell metabolism. 

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