Filamin A Modulates Store-Operated Ca 2+ Entry by Regulating STIM1 (Stromal Interaction Molecule 1)–Orai1 Association in Human Platelets
| Autor: | Jose Sanchez-Collado, Regis Bobe, Jose J. Lopez, Juan A. Rosado, Isaac Jardín, Letizia Albarran, Tarik Smani, Nuria Bermejo, Pedro C. Redondo |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Platelets
inorganic chemicals 0301 basic medicine Skin Neoplasms ORAI1 Protein Platelet Aggregation Filamins calcium signaling Filamin 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Serine Humans FLNA Protein Interaction Domains and Motifs Platelet Stromal Interaction Molecule 1 Melanoma Cytoskeleton Ion channel Calcium signaling phosphorylation ORAI1 Chemistry STIM1 Cyclic AMP-Dependent Protein Kinases Neoplasm Proteins Cell biology 030104 developmental biology 030220 oncology & carcinogenesis ion channel Phosphorylation Calcium Cardiology and Cardiovascular Medicine Ion Channel Gating Protein Binding |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 38:386-397 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE). Approach and Results— SOCE is a major mechanism for calcium influx controlled by the intracellular Ca 2+ stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood. Our results demonstrate that STIM1 interacts with FLNA on calcium store depletion in human platelets. The interaction is dependent on the phosphorylation of FLNA at Ser 2152 by the cAMP-dependent protein kinase. Impairment of FLNA phosphorylation and knockdown of FLNA expression using siRNA increased SOCE in platelets. Similarly, SOCE was significantly greater in FLNA-deficient melanoma M2 cells than in the FLNA-expressing M2 subclone A7. Expression of FLNA in M2 cells attenuated SOCE, an effect prevented when the cells were transfected with the nonphosphorylatable FLNA S2152A mutant. Transfection of M2 cells with the STIM1(K684,685E) mutant reduced the STIM1–FLNA interaction. In platelets, attenuation of FLNA expression using siRNA resulted in enhanced association of STIM1 with the cytoskeleton, greater STIM1–Orai1 interaction, and SOCE. Introduction of an anti-FLNA (2597–2647) antibody attenuated the STIM1–FLNA interaction and enhanced thrombin-induced platelet aggregation. Conclusions— Our results indicate that FLNA modulates SOCE and then the correct platelet function, by fine-tuning the distribution of STIM1 in the cytoskeleton and the interaction with Orai1 channels. |
| Databáze: | OpenAIRE |
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