Stimulation of cell invasion by the Golgi Ion Channel GAAP/TMBIM4 via an H2O2-Dependent Mechanism

Abstract

The mechanisms by which the Golgi apparatus (GA) impacts on cell invasion are poorly understood. The human Golgi Anti-Apoptotic Protein (hGAAP, also known as TMBIM4) is a highly conserved Golgi cation channel that modulates intracellular Ca2+ fluxes. Human GAAP is expressed in all human tissues, is essential for cell viability and provides resistance against a range of apoptotic stresses. Furthermore, hGAAP enhances adhesion and cell migration by increasing the turnover of focal adhesions due to activation of store-operated Ca2+ entry.Here, we describe a GA-derived mechanism that controls cell invasion. The overexpression of hGAAP stimulates 3-dimensional proteolytic cell invasion by a mechanism that is dependent on the accumulation of intracellular hydrogen peroxide, which might be produced by the hGAAP-dependent stimulation of mitochondrial respiration.These findings provide new insight into the complex mechanisms by which Ca2+ and reactive oxygen species signaling contribute to cell invasion and to the role of the GA in these processes. Keywords: Calcium, Cell invasion, TMBIM, Golgi apparatus, Hydrogen peroxide, Metabolism