Open AccessOncogenic K-Ras suppresses IP3-dependent Ca2+ release through remodeling of IP3Rs isoform composition and ER luminal Ca2+ levels in colorectal cancer cell lines
Author(s) -
Cristina Pierro,
Simon J. Cook,
Thomas Foets,
Martin D. Bootman,
H. Llewelyn Roderick
Publication year - 2014
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.141408
Subject(s) - biology , microbiology and biotechnology , signal transduction , receptor tyrosine kinase , receptor , gene isoform , kinase , genetics , gene
The GTPase Ras is a molecular switch engaged downstream of G-protein coupled receptors and receptor tyrosine kinases that controls multiple cell fate-determining signalling pathways. Ras signalling is frequently deregulated in cancer underlying associated changes in cell phenotype. Although Ca2+ signalling pathways control some overlapping functions with Ras, and altered Ca2+ signalling pathways are emerging as important players in oncogenic transformation, how Ca2+ signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca2+ signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the mutated K-Ras allele (G13D) has been deleted by homologous recombination. We show that agonist-induced Ca2+ release from intracellular stores is enhanced by loss of K-RasG13D through an increase in the ER store content and a modification of IP3R subtype abundance. Consistently, uptake of Ca2+ into mitochondria and sensitivity to apoptosis was enhanced as a result of K-RasG13D loss. These results suggest that suppression of Ca2+ signalling is a common response to naturally occurring levels of K-RasG13D that contributes to a survival advantage during oncogenic transformation.