Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are evolutionarily conserved subcellular structures where the ER is closely apposed to the PM. Emerging evidence suggests that ER-PM junctions are important for Ca2+ signaling and lipid metabolism. Nevertheless, the specific functions and regulation of ER-PM junctions remain unclear. We are particularly interested in the role of ER-PM junctions during receptor-induced cell signaling. Receptor stimulation triggers the hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) at the PM and the release of Ca2+ in the ER to activate cellular functions including proliferation, migration and secretion. To sustain cell signaling and maintain cell homeostasis, inter-organelle signaling between the ER and the PM is crucial to quickly replenish PM PIP2 and ER Ca2+ with PI in the ER and Ca2+ in the extracellular space, respectively. We have previously identified three proteins, Nir2, E-Syt1 and STIM1, involved in the replenishment of PM PIP2 and ER Ca2+ and localized to ER-PM junctions following receptor stimulation. The objective of this proposal is to investigate the mechanisms of how PIP2 and Ca2+ homeostasis are regulated by dynamic translocation of Nir2, E-Syt1 and STIM1 to ER-PM junctions during receptor-induced cell signaling. We will use molecular, biochemical and genetic approaches in combination with cutting-edge live-cell imaging and EM for the proposed studies. In addition, we will develop innovative tools to monitor signaling events at ER-PM junctions and manipulate selected pools of lipids involved in PIP2 homeostasis.
In aim 1, we will determine how PM PIP2 is replenished by dynamic translocation of Nir2 to ER-PM junctions following receptor- induced hydrolysis.
In aim 2, we will determine how ER-PM junctions are regulated by dynamic translocation of E-Syt1 following receptor-induced cytosolic Ca2+ increases.
In aim 3, we will determine how store-operated Ca2+ entry is regulated by dynamic translocation of STIM1 to ER-PM junctions following ER Ca2+ depletion. We expect the proposed research will establish new paradigms for inter-organelle signaling at membrane junctions and will have a major impact on the fundamental concepts in cell biology and signal transduction.

Public Health Relevance

The communication between the endoplasmic reticulum (ER) and the plasma membrane (PM) is essential for cell functions such as Ca2+ signaling and lipid metabolism. Disruption of signal transduction at ER-PM junctions is associated with life-threatening diseases including severe combined immunodeficiency and muscular dystrophy. We propose to use cutting-edge imaging techniques and innovative molecular tools in combination with biochemical and genetic approaches to investigate the functions and regulation of ER-PM junctions. This work will greatly expand our understanding of cell signaling and will potentially lead to new approaches for treatment of human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Flicker, Paula F
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Chang, Chi-Lun; Chen, Yu-Ju; Quintanilla, Carlo Giovanni et al. (2018) EB1 binding restricts STIM1 translocation to ER-PM junctions and regulates store-operated Ca2+ entry. J Cell Biol 217:2047-2058
Kuo, Yi-Chun; He, Xiaojing; Coleman, Andrew J et al. (2018) Structural analyses of FERM domain-mediated membrane localization of FARP1. Sci Rep 8:10477
Hsieh, Ting-Sung; Chen, Yu-Ju; Chang, Chi-Lun et al. (2017) Cortical actin contributes to spatial organization of ER-PM junctions. Mol Biol Cell 28:3171-3180
Chen, Yu-Ju; Chang, Chi-Lun; Lee, Wan-Ru et al. (2017) RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P2. J Cell Biol 216:2011-2025
Chang, Chi-Lun; Liou, Jen (2016) Homeostatic regulation of the PI(4,5)P2-Ca(2+) signaling system at ER-PM junctions. Biochim Biophys Acta 1861:862-873
Liou, Jen; Chang, Chi-Lun (2015) Unveiling physiological functions of extended synaptotagmins. Cell Cycle 14:799-800