Regulation of the EGFR endocytic route by an Endoplasmic Reticulum-related Ca2+ binding protein.

EGFR is a receptor-type tyrosine kinase exposed on the surface of epithelial cells, mediating responses to EGF family ligands via a complex signaling path-way. The binding of EGF ligand to EGFR induces its activation and internaliza-tion, stimulating multiple intracellular signaling cascades including the Ras/MAP kinase, phospholipase Cγ/protein kinase C, phosphatidylinositol 3-kinase (PI3K)/Akt, Jak/STAT, and Src family kinases. Since all these pathways are in-volved in cell proliferation, differentiation, migration, and survival, EGFR plays an important role at both physiological and pathological levels. Overexpression and/or genetic alteration of the EGFR gene are indeed strictly associated with carcinogenesis1,2. The endocytic trafficking of EGFR is regulated by two mechanisms, i.e. clathrin-mediated endocytosis (CME) and non-clathrin-mediated endocytosis pathways (NCE), that are responsible for EGFR recycling or intracellular degradation. Many studies have reported that at low doses of EGF ligand, EGFR is recycled back to the plasma membrane, while at high concentration of EGF is carried to the lysosomes for degradation. In this context, the release of intracellular calci-um from the Endoplasmic Reticulum (ER) to the cytosol, upon EGF-EGFR bind-ing, plays a critical role in EGFR recycling and degradation3. In our study, we investigated the role of a SERCA-regulating calcium-binding protein in the EGFR recycling in Non-Small Lung Cancer cells. We evidenced an accumulation of EGFR protein in Golgi apparatus, a down-regulation of AKT pathway, and a reduction in cellular migration capability, up-on silencing of this SERCA-regulating calcium-binding protein. Moreover, the silencing of this protein cooperates with an EGFR inhibitor in reducing the mi-gratory capability of these cells. Altogether these data highlight the relevance of the ER-related calcium-binding proteins in the regulation of EGFR recycling and EGFR downstream pathways. In conclusion, we suggest a possible novel functional approach to modulate the EGFR signaling pathway.