Calcium Signalling
Cancer-causing mutations disrupt the homeostasis of normal cells, and remodel it to promote survival of the cancerous cells. Among many factors that control cellular homeostasis, the calcium ion (Ca2+) is a vital second messenger in the cell, whose concentration is tightly regulated, such that it generates cellular signals in response to external stimuli. Utilizing Ca2+signal pathways, metastatic cancer cells develop an enhanced propensity to migrate, and effectively detach from the tumour, enter the circulation system, and re-establish secondary growth in distant organs. The Ca2+ signalling pathway responsible for cancer metastasis appears to involve Orai1, and stromal interaction molecule 1 (STIM1), which are downstream of the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), G-protein-coupled receptors and receptor tyrosine kinases. Recent studies have revealed that Ca2+ high/STIM2 low expression. These molecular alterations in cancer cells lead to remodeling of intracellular Ca2+ homeostasis, resulting in altered gene expression in the cell. Interestingly, a point mutation of Orai1 (R91W) was identified in patients with the severe combined immune deficiency syndrome (SCID) and this mutation was found to impair Ca2+-release-activated Ca2+ (CRAC) activity. In order to understand how the concentration of 2+ in the cell is regulated in both a spatial and a temporal manner, and how this affects gene expression in cancer cells, we need to better understand the roles and precise regulatory mechanisms of various 2+ transporters (i.e., Ca2+ channels and Ca2+ pumps).
Derler I, Jardin I, Stathopulos PB, Muik M, Fahrner M, Zayats V, Pandey SK, Poteser M, Lackner B, Absolonova M, Schindl R, Groschner K, Ettrich R, Ikura M, Romanin C. Cholesterol modulates Orai1 channel function. (2016) Sci Signal. 9(412):ra10
Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. (2013) Nature Commun. 4:2963.
Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA, Dale P, Li C, Ames JB, Ikura M, Taylor CW. Structural and functional conservation of key domains in InsP3 and ryanodine receptors. (2012) Nature 483(7387):108-12.
Muik M, Fahrner M, Schindl R, Stathopulos P, Frischauf I, Derler I, Plenk P, Lackner B, Groschner K, Ikura M, Romanin C. STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation. (2011) EMBO J. 30(9):1678-89.
Zheng L, Stathopulos PB, Schindl R, Li GY, Romanin C, Ikura M. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. (2011) Proc Natl Acad Sci USA. 108(4): 1337-42.
Amador FJ, Liu S, Ishiyama N, Plevin MJ, Wilson A, MacLennan DH, Ikura M. Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop. (2009) Proc Natl Acad Sci U S A. 106(27):11040-4.
Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. (2008) Cell, 135(1): 110-22.
Ikura, M. Ames, J.B. Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: two ways to promote multifunctionality (2006) Proc Natl Acad Sci USA. 103(5):1159-64.
Bosanac I, Yamazaki H, Matsu-Ura T, Michikawa T, Mikoshiba K, Ikura M. Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor. (2005) Mol Cell, Jan. 21;17(2): 193-203.