Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodelling of IP₃Rs isoform composition and ER luminal Ca²⁺ levels in colorectal cancer cell lines

Pierro, Cristina; Cook, Simon J.; Foets, Thomas C. F.; Bootman, Martin D. and Roderick, H. Llewelyn (2014). Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodelling of IP₃Rs isoform composition and ER luminal Ca²⁺ levels in colorectal cancer cell lines. Journal of Cell Science, 127(7) pp. 1607–1619.

DOI: https://doi.org/10.1242/jcs.141408

Abstract

The GTPase Ras is a molecular switch engaged downstream of G-protein coupled receptors and receptor tyrosine inases that controls multiple cell fate-determining signalling athways. 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-Ras^G13D 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 KRas^G13D loss. These results suggest that suppression of Ca²⁺ signalling is a common response to naturally occurring levels of K-Ras^G13D that contributes to a survival advantage during oncogenic transformation.

Viewing alternatives

Metrics

Item Actions

Export

You can export this page using these formats Digital Object Identifier - DOI

About

• Item ORO ID
• 39535
• Item Type
• Journal Item
• ISSN
• 1477-9137
• Keywords
• K-Ras; cancer; Inositol 1,4,5-triphosphate/IP3; Ca2+; mitochondria
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Research Group
• Cancer Research Group
• Copyright Holders
• © 2014 Published by The Company of Biologists Ltd.
• Depositing User
• Martin Bootman