Two-pore channels affect EGF receptor signaling by receptor trafficking and expression

Two-pore channels (TPCs) are key components for regulating Ca²⁺ current from endosomes and lysosomes to the cytosol. This locally restricted Ca²⁺ current forms the basis for fusion and fission events between endolysosomal membranes and thereby for intracellular trafficking processes. Here, we study the function of TPC1 and TPC2 for uptake, recycling, and degradation of epidermal growth factor receptor (EGFR) using a set of TPC knockout cells. RNA sequencing analysis revealed multiple changes in the expression levels of EGFR pathway-related genes in TPC1-deficient cells. We propose that a prolonged presence of activated EGFRs in endolysosomal signaling platforms, caused by genetic inactivation of TPCs, does not only affect EGFR signaling pathways but also increases de novo synthesis of EGFR. Increased basal phospho-c-Jun levels contribute to the high EGFR expression in TPC-deficient cells. Our data point to a role of TPCs not only as important regulators for the EGFR transportation network but also for EGFR-signaling and expression.