Cell spreading controls endoplasmic and nuclear calcium: A physical gene regulation pathway from the cell surface to the nucleus

Cells attaching to an extracellular matrix through integrins flatten out (spread) on the matrix, eliciting cellular signals needed for survival. We show that the shape of the nucleus changes and the nuclear calcium level increases in spreading cells. Moreover, cell spreading and osmotic stretching of isolated nuclei cause release of perinuclear Ca2+, and patch clamping of nuclei reveals stretch-activated Ca2+ permeable channels. Gene expression assays with myocyte enhancer factor 2, which is activated by calmodulin-dependent kinase IV, indicate that the elevation in nuclear Ca2+ is functionally significant. We propose a mechano-transduction pathway in which spreading-induced nuclear stretching releases Ca2+ from the perinuclear space, and the resulting Ca2+ elevation in the nucleus provokes changes in gene expression.