Conférence de Sara Sigismund de l'European Institute of Oncology

En raison des restrictions de voyage des habitants de Lombardie, le séminaire de la professeure Sigismund est annulé. Une date ultérieure sera trouvée pour sa venue.

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, while clathrin-mediated endocytosis (CME) is mainly involved in EGFR recycling and sustaining signalling, EGFR internalization through non-clathrin endocytosis (NCE) leads primarily to receptor degradation and signal extinction, representing a crucial safety mechanism to protect cells from overstimulation. Internalization via NCE involves the formation of tripartite contact sites between the PM, the endoplasmic reticulum (ER) and the mitochondria, where EGF-dependent localized Ca2+ signalling occurs and propagate. Ca2+ release is in turn needed for the fission of NCE vesicular structures and their release in the cytosol. Thus, NCE, by targeting EGFRs to degradation, restricts EGFR signalling; it also exerts a positive role in promoting localized Ca2+ signalling, possibly activating a wider cellular response and regulating cellular processes that extend beyond those associated with the canonical EGFR signalling pathway. Through a combination of mathematical modelling and wet-lab experiments, we are currently elucidating how the integration of distinct endocytic pathways and inter-organelle crosstalk regulate the EGFR physiological responses and which are the molecular circuitries involved.

EGFR signalling talks to mitochondria through contact sites
By Prof. Sara Sigismund (European Institute of Oncology IRCCS, Milan / University of Milan)