STIM1 (stromal interaction molecule 1) is a key regulator of store-operated calcium entry (SOCE). Upon depletion of Ca2+ concentration within the endoplasmic reticulum (ER), STIM1 relocalizes at ER-plasma membrane junctions, activating store-operated calcium channels (SOCs). Although one knows the molecular details for STIM1-SOCs binding, the regulation of SOCE remains largely unknown. A detailed list of phosphoresidues within the STIM1 sequence has been reported. However, the molecular pathways controlling this phosphorylation and its function are still under study. Using phospho-specific antibodies, it is demonstrated here that ERK1/2 mediates STIM1 phosphorylation at Ser575, Ser608, and Ser621 during Ca2+ store depletion, and that Ca2+ entry and store refilling restore phosphorylation to basal levels. This phosphorylation occurs in parallel to the dissociation from end-binding protein 1 (EB1), a regulator of growing microtubule ends. While Ser to Ala mutation of residues 575, 608, and 621 showed a constitutive binding to EB1 even after Ca2+ store depletion, Ser to Glu mutation of these residues, to mimic the phosphorylation profile attained after store depletion, triggered full dissociation from EB1. Given that wild-type STIM1 and STIM1S575E/S608E/S621E activate SOCE similarly, a model is proposed to explain how ERK1/2-mediated phosphorylation of STIM1 regulates SOCE. This regulation is based on the phosphorylation of STIM1 to trigger dissociation from EB1 during Ca2+ store depletion, an event that is fully reverted by Ca2+ entry and store refilling.
Phosphorylation of STIM1 at ERK1/2 Target sites regulates the interaction with the microtubule plus-end binding protein EB1
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Eulalia Pozo-Guisado, Vanessa Casas-Rua, Patricia Tomas-Martin, Aida M. Lopez-Guerrero, Alberto Alvarez-Barrientos, Francisco Javier Martin-Romero; Phosphorylation of STIM1 at ERK1/2 Target sites regulates the interaction with the microtubule plus-end binding protein EB1. J Cell Sci 2013; jcs.125054. doi: https://doi.org/10.1242/jcs.125054
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