Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 1, Pages 51-61Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.056424
Keywords
R-Ras; Calpain; Cell adhesion; Endoplasmic reticulum; Integrins
Categories
Funding
- British Heart Foundation
- Chief Scientist Office, Scotland
- Wellcome Trust
- Medical Research Council [G9900991B] Funding Source: researchfish
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The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multitrans-membrane domain protein Fam38A, located at the endoplasmic reticulum ( ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous beta 1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca(2+) release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.
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