Determination of Protein copy number, slow feedback loops, and protein-protein interaction in the store operated calcium signalling network
Final Report Abstract
Despite large cell‐to‐cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca2+ levels and adjust in parallel the concentrations of the store‐operated Ca2+ influx mediator stromal interaction molecule (STIM), the plasma membrane Ca2+ pump plasma membrane Ca–ATPase (PMCA), and the ER Ca2+ pump sarco/ER Ca2+–ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca2+ levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks.
Publications
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Parallel adaptive feedback enhances reliability of the Ca2+ signaling system. Proc Natl Acad Sci USA. 2011
Abell E & Ahrends R, Bandara S, Park BO, Teruel MN
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Consecutive positive feedback loops create a bistable switch that controls preadipocyte-to-adipocyte conversion. Cell Rep. 2012
Park BO, Ahrends R, Teruel MN
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Controlling low rates of terminal cell differentiation through noise and ultra-high feedback. The FASEB Journal, Vol. 28, No. 1_supplement
April 2014
Mary Teruel, Robert Ahrends, Asuka Ota, Kyle Kovary, and Byung Ouk Park
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Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep. 2014 Jan 16;6(1):168-81
Niewiadomski P, Kong JH, Ahrends R, Ma Y, Humke EW, Khan S, Teruel MN, NovitchBG, Rohatgi R
