Soluble αKlotho downregulates Orai1-mediated store-operated Ca2+ entry via PI3K-dependent signaling
| Autor: | Ji Hee Kim, Seung Kuy Cha, Kyu Sang Park, Seong Jin Choi, Kyu Hee Hwang, Eun Young Park |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Premature aging ORAI1 Protein Physiology STIM1 Clinical Biochemistry Down-Regulation Exocytosis 03 medical and health sciences chemistry.chemical_compound Phosphatidylinositol 3-Kinases 0302 clinical medicine FGF23 Physiology (medical) Cell Line Tumor Humans Calcium Signaling Stromal Interaction Molecule 1 Klotho Klotho Proteins PI3K/AKT/mTOR pathway Chemistry ORAI1 Brefeldin A CRAC channel Cell biology Neoplasm Proteins 030104 developmental biology Ion homeostasis HEK293 Cells 030220 oncology & carcinogenesis Calcium Ion Channels Receptors and Transporters SOCE |
| Zdroj: | Pflugers Archiv |
| ISSN: | 1432-2013 0031-6768 |
| Popis: | αKlotho is a type 1 transmembrane anti-aging protein. αKlotho-deficient mice have premature aging phenotypes and an imbalance of ion homeostasis including Ca2+ and phosphate. Soluble αKlotho is known to regulate multiple ion channels and growth factor-mediated phosphoinositide-3-kinase (PI3K) signaling. Store-operated Ca2+ entry (SOCE) mediated by pore-forming subunit Orai1 and ER Ca2+ sensor STIM1 is a ubiquitous Ca2+ influx mechanism and has been implicated in multiple diseases. However, it is currently unknown whether soluble αKlotho regulates Orai1-mediated SOCE via PI3K-dependent signaling. Among the Klotho family, αKlotho downregulates SOCE while βKlotho or γKlotho does not affect SOCE. Soluble αKlotho suppresses serum-stimulated SOCE and Ca2+ release-activated Ca2+ (CRAC) channel currents. Serum increases the cell-surface abundance of Orai1 via stimulating vesicular exocytosis of the channel. The serum-stimulated SOCE and cell-surface abundance of Orai1 are inhibited by the preincubation of αKlotho protein or PI3K inhibitors. Moreover, the inhibition of SOCE and cell-surface abundance of Orai1 by pretreatment of brefeldin A or tetanus toxin or PI3K inhibitors prevents further inhibition by αKlotho. Functionally, we further show that soluble αKlotho ameliorates serum-stimulated SOCE and cell migration in breast and lung cancer cells. These results demonstrate that soluble αKlotho downregulates SOCE by inhibiting PI3K-driven vesicular exocytosis of the Orai1 channel and contributes to the suppression of SOCE-mediated tumor cell migration. |
| Databáze: | OpenAIRE |
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