Sara Sigismund is Associate Professor at the University of Milan, and leads the Endocytosis Research team at the Dept. of Experimental Oncology, IEO, Milan. Since earning her PhD in Life Science in 2004, her long-standing research goal is to understand the role of endocytosis in the regulation of EGFR signaling. Through the elucidation of the molecular mechanisms governing EGFR ubiquitination and endocytosis, Sara’s work led to the discovery of a novel mechanism of non-clathrin endocytosis (NCE), involving contact sites between the endoplasmic reticulum and the plasma membrane that are critical for EGFR internalization at high ligand concentration. Receptors internalized by NCE are targeted to lysosomes for degradation leading to signal attenuation. Within the field of endocytosis, Sara’s work has helped establish the concept that integration of distinct endocytic pathways is critical for determining the final signaling output. Her current research interests include the elucidation of the molecular mechanism of EGFR-NCE, its interplay with mitochondrial functions and its functional significance in normal physiology and cancer.
Her work has received funding support from the European Research Council (ERC Consolidator Grant), The Worldwide Cancer Research, the Italian Association of Cancer Research (AIRC Investigator Grant), and the Italian Ministry of Education, University and Research.
About her talk: Contact sites between PM, ER and mitochondria: connecting EGFR signalling to cell metabolism
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. NCE involves contact sites between the PM, the endoplasmic reticulum and the mitochondria, that work as platforms for localized calcium signalling events. In my laboratory, we are currently elucidating how the integration of distinct endocytic pathways and inter-organelle crosstalk regulate EGFR signalling and its interplay with cell metabolic functions, through the use of a number of genetic tools and fluorescent/chemiluminescent-based probes to detect calcium signalling response at different cellular locations, as well as localized mitochondrial metabolic responses.