Extracellular secretagogin is internalized into the cells through endocytosis

Secretagogin (SCGN) is a calcium-sensor protein with a regulatory role in glucose metabolism and the secretion of several peptide hormones. Many, but not all, functions of SCGN can be explained by its intracellular manifestation. Despite early data on SCGN secretion, the secretory mechanism, biological fate, physiological implications and trans-cellular signalling of extracellular SCGN remain unknown. We here report that extracellular SCGN is readily internalized into the C2C12 cells in an energy-dependent manner. Using endocytosis inhibitors, we demonstrate that SCGN internalizes via clathrin-mediated endocytosis, following which, SCGN localizes largely in the cytosol. Exogenous SCGN treatment induces a global proteomic reprogramming in C2C12 cells. Gene ontology search suggests that SCGN-induced proteomic reprogramming favours protein synthesis and cellular growth. We thus validated the cell proliferative action of SCGN using C2C12, HepG2 and NIH-3T3 cell lines. Based on the data, we propose that circulatory SCGN is internalized into the target cells and modulates the expression of cell growth-related proteins. The work suggests that extracellular SCGN is a functional protein, which communicates with specific cell types and directly modulates cell proliferation.