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

doi:10.1073/pnas.0531397100

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

^*Cancer Research Center and ^‡The Del E. Webb Center for Neuroscience and Aging Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037

Contributed by Erkki Ruoslahti

Abstract

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.

Footnotes

↵ † Permanent address: Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
↵ § To whom correspondence should be addressed. E-mail: ruoslahti{at}burnham.org.
Abbreviations:

ECM,

extracellular matrix;

MEF2,

myocyte enhancer factor 2;

YC,

yellow cameleon;

ER,

endoplasmic reticulum;

InsP3,

inositol trisphosphate;

BAPTA,

1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate