Receptor-triggered cytosolic calcium (Ca2+) signals are ubiquitously used in signal transduction. In most cells, an initial Ca2+ signals can be induced by receptor-mediated activation of phospholipase C, the production of the second messenger IPS, and the release of Ca2+ from ER Ca2+-stores. Nevertheless, this transient IPS-mediated Ca2+-signal is typically not sufficient to induce long-term regulation of transcription, secretion and other important cellular processes. In addition, cell activation requires a Ca2+-store depletion triggered opening of plasma membrane Ca2+ channels. Our grant investigates this important but poorly understood """"""""store-operated Ca2+ signaling pathway"""""""" (SOC). Previous experimental evidence suggested that this ubiquitous signaling pathway begins in the lumen of the ER where an unkown Ca2+-sensor would monitor the loss of ER Ca2+ and then would signal to the plasma membrane to open more Ca2+-channels. During the last funding period, we discovered that STIM1 and STIM2 proteins function as Ca2+-sensors in the ER and that they are necessary and sufficient for signaling to the plasma membrane and opening SOC Ca2+-influx channels. This is the first molecular component that has been identified in this important cell signaling pathway. Our grant is focusing on these STIM proteins and on other regulators of the SOC signaling pathway that we have identified in subsequent siRNA screens using a human cell line. We will be using calcium imaging, fluorescence microscopy of protein distribution, biochemical approaches and mutant constructs of STIM and other identified regulators to dissect the mechanism of action of STIM proteins and other identified regulators in the regulation of SOC. We will also investigate the broader question of how this SOC signaling pathway participates in the balance of plasma membrane Ca2+-influx and Ca2+-export. Finally, we will develop a quantitative model of the global Ca2+ signaling network that integrates this new signaling pathway with other Ca2+-regulatory mechanisms. We will test our model by using siRNA perturbations and will compare the model predictions against measurements of the resulting changes in Ca2+-f luxes. Since this SOC influx pathway has been shown to be essential for many cellular processes such as T- and B-cell activation, mast cell activation and osteoclast differentiation, it is likely that our findings of new signaling components and regulatory processes in the SOC pathway will offer opportunities for developing novel drugs that improve pathological conditions such as transplant rejection, inflammation, allergies and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030179-27
Application #
7744702
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Jones, Warren
Project Start
1982-02-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
27
Fiscal Year
2010
Total Cost
$367,587
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Cappell, Steven D; Chung, Mingyu; Jaimovich, Ariel et al. (2016) Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry. Cell 166:167-80
Bajar, Bryce T; Lam, Amy J; Badiee, Ryan K et al. (2016) Fluorescent indicators for simultaneous reporting of all four cell cycle phases. Nat Methods 13:993-996
Winans, Amy M; Collins, Sean R; Meyer, Tobias (2016) Waves of actin and microtubule polymerization drive microtubule-based transport and neurite growth before single axon formation. Elife 5:e12387
Hayer, Arnold; Shao, Lin; Chung, Mingyu et al. (2016) Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol 18:1311-1323
Yang, Hee Won; Collins, Sean R; Meyer, Tobias (2016) Locally excitable Cdc42 signals steer cells during chemotaxis. Nat Cell Biol 18:191-201
Miyazaki, Yusuke; Mizumoto, Kota; Dey, Gautam et al. (2016) A method to rapidly create protein aggregates in living cells. Nat Commun 7:11689
Malmersjö, Seth; Di Palma, Serena; Diao, Jiajie et al. (2016) Phosphorylation of residues inside the SNARE complex suppresses secretory vesicle fusion. EMBO J 35:1810-21
Dey, Gautam; Meyer, Tobias (2015) Phylogenetic Profiling for Probing the Modular Architecture of the Human Genome. Cell Syst 1:106-15
Dey, Gautam; Jaimovich, Ariel; Collins, Sean R et al. (2015) Systematic Discovery of Human Gene Function and Principles of Modular Organization through Phylogenetic Profiling. Cell Rep :
Yang, Z J P; Broz, D Kenzelmann; Noderer, W L et al. (2015) p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress. Cell Death Differ 22:560-73

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