A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure
Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/41378 |
| _version_ | 1811227883270569984 |
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| author | Adam J Pollak Canzhao Liu Aparna Gudlur Joshua E Mayfield Nancy D Dalton Yusu Gu Ju Chen Joan Heller Brown Patrick G Hogan Sandra E Wiley Kirk L Peterson Jack E Dixon |
| author_facet | Adam J Pollak Canzhao Liu Aparna Gudlur Joshua E Mayfield Nancy D Dalton Yusu Gu Ju Chen Joan Heller Brown Patrick G Hogan Sandra E Wiley Kirk L Peterson Jack E Dixon |
| author_sort | Adam J Pollak |
| collection | DOAJ |
| description | Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here, we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology. |
| first_indexed | 2024-04-12T09:48:15Z |
| format | Article |
| id | doaj.art-ecc097f1b4894d6997ab24d9a2cc0ed7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:48:15Z |
| publishDate | 2018-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ecc097f1b4894d6997ab24d9a2cc0ed72022-12-22T03:37:53ZengeLife Sciences Publications LtdeLife2050-084X2018-12-01710.7554/eLife.41378A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failureAdam J Pollak0https://orcid.org/0000-0001-5266-4691Canzhao Liu1Aparna Gudlur2Joshua E Mayfield3Nancy D Dalton4Yusu Gu5Ju Chen6Joan Heller Brown7Patrick G Hogan8Sandra E Wiley9Kirk L Peterson10Jack E Dixon11https://orcid.org/0000-0002-8266-5449Department of Pharmacology, University of California, San Diego, San Diego, United StatesDepartment of Medicine, University of California, San Diego, San Diego, United StatesDivision of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, San Diego, United StatesDepartment of Pharmacology, University of California, San Diego, San Diego, United StatesDepartment of Medicine, University of California, San Diego, San Diego, United StatesDepartment of Medicine, University of California, San Diego, San Diego, United StatesDepartment of Medicine, University of California, San Diego, San Diego, United StatesDepartment of Pharmacology, University of California, San Diego, San Diego, United StatesDivision of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, San Diego, United States; Program in Immunology, University of California, San Diego, San Diego, United States; Moores Cancer Center, University of California, San Diego, San Diego, United StatesDepartment of Pharmacology, University of California, San Diego, San Diego, United StatesDepartment of Medicine, University of California, San Diego, San Diego, United StatesDepartment of Pharmacology, University of California, San Diego, San Diego, United States; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States; Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, United StatesCa2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here, we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology.https://elifesciences.org/articles/41378protein kinasecalciumheart diseaseStim 1calsequestrin 2 |
| spellingShingle | Adam J Pollak Canzhao Liu Aparna Gudlur Joshua E Mayfield Nancy D Dalton Yusu Gu Ju Chen Joan Heller Brown Patrick G Hogan Sandra E Wiley Kirk L Peterson Jack E Dixon A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure eLife protein kinase calcium heart disease Stim 1 calsequestrin 2 |
| title | A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure |
| title_full | A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure |
| title_fullStr | A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure |
| title_full_unstemmed | A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure |
| title_short | A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure |
| title_sort | secretory pathway kinase regulates sarcoplasmic reticulum ca2 homeostasis and protects against heart failure |
| topic | protein kinase calcium heart disease Stim 1 calsequestrin 2 |
| url | https://elifesciences.org/articles/41378 |
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