Highlight Publication February 2008

Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L, Chastre E, Khan F, Landegren U, Soderberg O, Bootman MD, Roderick HL.
Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis.
Proceedings of the National Academy of Sciences of the United States of America 105 2427-2432
http://dx.doi.org/10.1073/pnas.0711324105

Lay Description

Cancer arises through an imbalance in cell proliferation and death, which results in an increase in cell numbers and tumour formation. Both cell proliferation and death are controlled by intracellular signalling pathways, which either suppress the activity of pro-death pathways or promote cell division. In cancer, as a result of mutations in their DNA sequence, the activity of the proteins involved in these processes is altered and pathology ensues.

Two of the key signalling pathways involved in controlling cell death and survival are regulated by increases in intracellular calcium and the activity of the lipid-activated protein kinase, protein kinase B (PKB; otherwise known as Akt) respectively. Specifically, increases in intracellular calcium can promote cell death, whereas, by inactivating pro-death pathways, enhanced PKB activity suppresses cell death. Indeed, augmented PKB activity is a common hallmark of many cancers.

Over the past several years, intracellular calcium signals generated as a result of release via inositol 1,4,5-trisphosphtase receptor channels (InsP3Rs) on intracellular calcium stores, localized in the endoplasmic reticulum, have been implicated in cell death processes. In this article by Szado et al, InsP3Rs have been discovered to be a new target of PKB to promote cell survival. Specifically, by analyzing the DNA sequence coding for the InsP3Rs, Szado and co-workers identified a motif that was found in other proteins to be recognised by PKB. Szado and co-workers have now determined that PKB did in fact modify the receptor protein resulting in a reduction in its ability to act as a calcium channel. As a result, cells were protected from death when faced with a pro-death stimulus. This effect of PKB modulation of InsP3R activity and cell survival was most notably also observed in cells that were cancerous due to a genetic mutation that had lead to an increase PKB activity. The data presented in this study also suggest that regulation of InsP3R activity may be one of the more dominant mechanisms by which PKB elicits its pro-survival effects

Together, these findings have important implications for understanding the signalling roles of both calcium and PKB in controlling cell death, growth, division and proliferation. In addition, these findings suggest that intervening in the PKB-InsP3R interaction would constitute a new target for therapeutic intervention in the treatment of cancers where PKB is known to be involved.

About the Lead Author

Tania Szado obtained her Ph.D. from the University of British Columbia, Canada where she studied calcium signalling in vascular smooth muscle in the laboratory of Dr. Cornelis van Breemen.  She then moved on to work as a research scientist with Medigene in Munich, Germany before commencing postdoctoral training in 2004 with Martin Bootman and Llewelyn Roderick at the Babraham Institute on a BBSRC funded grant.  At the end of 2007, she moved to work for Roche Pharmaceuticals as a co-lab head in their pre-clinical toxicology division in Basel, Switzerland. Tania is currently moving into a new role as a clinical science specialist within the Roche oncology group in Welwyn Garden City, UK.